Crystal structures of the M1 and M4 muscarinic acetylcholine receptors
Abstract
Muscarinic M1–M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer’s disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. In this paper, we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. Finally, we also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.
- Authors:
-
- Monash Univ., Melbourne, VIC (Australia). Monash Inst. of Pharmaceutical Sciences. Drug Discovery Biology. Dept. of Pharmacology
- ConfometRx, Santa Clara, CA (United States)
- Eli Lilly, Indianapolis, IN (United States). Dept. of Neuroscience
- Eli Lilly, Indianapolis, IN (United States). Dept. of Computational Chemistry and Chemoinformatics
- Eli Lilly, Windlesham (United Kingdom). Dept. of Computational Chemistry and Chemoinformatics
- Stanford Univ., CA (United States). School of Medicine. Dept. of Molecular and Cellular Physiology. Dept. of Structural Biology
- ConfometRx, Santa Clara, CA (United States); Stanford Univ., CA (United States). School of Medicine. Dept. of Molecular and Cellular Physiology
- Publication Date:
- Research Org.:
- Stanford Univ., CA (United States); Monash Univ., Melbourne, VIC (Australia)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States); Lilly Research Award Program (United States); Mathers Foundation (United States); National Health and Medical Research Council (NHMRC) (Australia)
- Contributing Org.:
- ConfometRx, Santa Clara, CA (United States); Eli Lilly, Indianapolis, IN (United States); Eli Lilly, Windlesham (United Kingdom)
- OSTI Identifier:
- 1248385
- Grant/Contract Number:
- W-31-109-ENG-38; Y1-CO-1020; Y1-GM-1104; APP1055134
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 531; Journal Issue: 7594; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; X-ray crystallography; G protein-coupled receptors
Citation Formats
Thal, David M., Sun, Bingfa, Feng, Dan, Nawaratne, Vindhya, Leach, Katie, Felder, Christian C., Bures, Mark G., Evans, David A., Weis, William I., Bachhawat, Priti, Kobilka, Tong Sun, Sexton, Patrick M., Kobilka, Brian K., and Christopoulos, Arthur. Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. United States: N. p., 2016.
Web. doi:10.1038/nature17188.
Thal, David M., Sun, Bingfa, Feng, Dan, Nawaratne, Vindhya, Leach, Katie, Felder, Christian C., Bures, Mark G., Evans, David A., Weis, William I., Bachhawat, Priti, Kobilka, Tong Sun, Sexton, Patrick M., Kobilka, Brian K., & Christopoulos, Arthur. Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. United States. https://doi.org/10.1038/nature17188
Thal, David M., Sun, Bingfa, Feng, Dan, Nawaratne, Vindhya, Leach, Katie, Felder, Christian C., Bures, Mark G., Evans, David A., Weis, William I., Bachhawat, Priti, Kobilka, Tong Sun, Sexton, Patrick M., Kobilka, Brian K., and Christopoulos, Arthur. Wed .
"Crystal structures of the M1 and M4 muscarinic acetylcholine receptors". United States. https://doi.org/10.1038/nature17188. https://www.osti.gov/servlets/purl/1248385.
@article{osti_1248385,
title = {Crystal structures of the M1 and M4 muscarinic acetylcholine receptors},
author = {Thal, David M. and Sun, Bingfa and Feng, Dan and Nawaratne, Vindhya and Leach, Katie and Felder, Christian C. and Bures, Mark G. and Evans, David A. and Weis, William I. and Bachhawat, Priti and Kobilka, Tong Sun and Sexton, Patrick M. and Kobilka, Brian K. and Christopoulos, Arthur},
abstractNote = {Muscarinic M1–M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer’s disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. In this paper, we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. Finally, we also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.},
doi = {10.1038/nature17188},
journal = {Nature (London)},
number = 7594,
volume = 531,
place = {United States},
year = {Wed Mar 09 00:00:00 EST 2016},
month = {Wed Mar 09 00:00:00 EST 2016}
}
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Works referenced in this record:
Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development
journal, September 2007
- Wess, Jürgen; Eglen, Richard M.; Gautam, Dinesh
- Nature Reviews Drug Discovery, Vol. 6, Issue 9
The role of acetylcholine in learning and memory
journal, December 2006
- Hasselmo, Michael E.
- Current Opinion in Neurobiology, Vol. 16, Issue 6
Cholinergic Modulation of Cortical Function
journal, January 2006
- Hasselmo, M. E.; Giocomo, L. M.
- Journal of Molecular Neuroscience, Vol. 30, Issue 1-2
Muscarinic acetylcholine receptors: novel opportunities for drug development
journal, June 2014
- Kruse, Andrew C.; Kobilka, Brian K.; Gautam, Dinesh
- Nature Reviews Drug Discovery, Vol. 13, Issue 7
Muscarinic acetylcholine receptor X-ray structures: potential implications for drug development
journal, June 2014
- Kruse, Andrew C.; Hu, Jianxin; Kobilka, Brian K.
- Current Opinion in Pharmacology, Vol. 16
Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia
journal, August 2008
- Shekhar, Anantha; Potter, William Z.; Lightfoot, Jeffrey
- American Journal of Psychiatry, Vol. 165, Issue 8
Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease
journal, April 1997
- Bodick, N. C.; Offen, W. W.; Levey, A. I.
- Archives of Neurology, Vol. 54, Issue 4
Pharmacological comparison of muscarinic ligands: Historical versus more recent muscarinic M1-preferring receptor agonists
journal, March 2009
- Heinrich, Julia N.; Butera, John A.; Carrick, Tikva
- European Journal of Pharmacology, Vol. 605, Issue 1-3
Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
journal, January 2009
- Jeffrey Conn, P.; Christopoulos, Arthur; Lindsley, Craig W.
- Nature Reviews Drug Discovery, Vol. 8, Issue 1
Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders
journal, January 2010
- Digby, Gregory J.; Shirey, Jana K.; Conn, P. Jeffrey
- Molecular BioSystems, Vol. 6, Issue 8
Allosteric modulation of G protein-coupled receptors: A pharmacological perspective
journal, January 2011
- Keov, Peter; Sexton, Patrick M.; Christopoulos, Arthur
- Neuropharmacology, Vol. 60, Issue 1
Impact of species variability and ‘probe-dependence’ on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor: Species variability in M4 receptor allosterism
journal, March 2011
- Suratman, S.; Leach, K.; Sexton, Pm
- British Journal of Pharmacology, Vol. 162, Issue 7
Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties
journal, November 2009
- Leach, Katie; Loiacono, Richard E.; Felder, Christian C.
- Neuropsychopharmacology, Vol. 35, Issue 4
Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia
journal, August 2008
- Chan, W. Y.; McKinzie, D. L.; Bose, S.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 31
A Selective Allosteric Potentiator of the M1 Muscarinic Acetylcholine Receptor Increases Activity of Medial Prefrontal Cortical Neurons and Restores Impairments in Reversal Learning
journal, November 2009
- Shirey, J. K.; Brady, A. E.; Jones, P. J.
- Journal of Neuroscience, Vol. 29, Issue 45
Selective activation of the M 1 muscarinic acetylcholine receptor achieved by allosteric potentiation
journal, August 2009
- Ma, Lei; Seager, Matthew A.; Wittmann, Marion
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 37
Molecular Determinants of Allosteric Modulation at the M 1 Muscarinic Acetylcholine Receptor
journal, January 2014
- Abdul-Ridha, Alaa; López, Laura; Keov, Peter
- Journal of Biological Chemistry, Vol. 289, Issue 9
Mechanistic Insights into Allosteric Structure-Function Relationships at the M 1 Muscarinic Acetylcholine Receptor
journal, October 2014
- Abdul-Ridha, Alaa; Lane, J. Robert; Mistry, Shailesh N.
- Journal of Biological Chemistry, Vol. 289, Issue 48
The Role of Transmembrane Domain 3 in the Actions of Orthosteric, Allosteric, and Atypical Agonists of the M 4 Muscarinic Acetylcholine Receptor
journal, February 2011
- Leach, Katie; Davey, Anna E.; Felder, Christian C.
- Molecular Pharmacology, Vol. 79, Issue 5
Structural Determinants of Allosteric Agonism and Modulation at the M 4 Muscarinic Acetylcholine Receptor : IDENTIFICATION OF LIGAND-SPECIFIC AND GLOBAL ACTIVATION MECHANISMS
journal, April 2010
- Nawaratne, Vindhya; Leach, Katie; Felder, Christian C.
- Journal of Biological Chemistry, Vol. 285, Issue 25
Structure and dynamics of the M3 muscarinic acetylcholine receptor
journal, February 2012
- Kruse, Andrew C.; Hu, Jianxin; Pan, Albert C.
- Nature, Vol. 482, Issue 7386
Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist
journal, January 2012
- Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu
- Nature, Vol. 482, Issue 7386
Crystallizing membrane proteins using lipidic mesophases
journal, April 2009
- Caffrey, Martin; Cherezov, Vadim
- Nature Protocols, Vol. 4, Issue 5
Fusion Partner Toolchest for the Stabilization and Crystallization of G Protein-Coupled Receptors
journal, June 2012
- Chun, Eugene; Thompson, Aaron A.; Liu, Wei
- Structure, Vol. 20, Issue 6
Modified T4 Lysozyme Fusion Proteins Facilitate G Protein-Coupled Receptor Crystallogenesis
journal, November 2014
- Thorsen, Thor Seneca; Matt, Rachel; Weis, William I.
- Structure, Vol. 22, Issue 11
Molecular architecture of G protein-coupled receptors
journal, January 1996
- van Rhee, A. Michiel; Jacobson, Kenneth A.
- Drug Development Research, Vol. 37, Issue 1
Transmembrane Domains 4 and 7 of the M 1 Muscarinic Acetylcholine Receptor Are Critical for Ligand Binding and the Receptor Activation Switch
journal, July 2001
- Lu, Zhi-Liang; Saldanha, Jose W.; Hulme, Edward C.
- Journal of Biological Chemistry, Vol. 276, Issue 36
Roof and Floor of the Muscarinic Binding Pocket: Variations in the Binding Modes of Orthosteric Ligands
journal, September 2007
- Goodwin, J. Alex; Hulme, Edward C.; Langmead, Christopher J.
- Molecular Pharmacology, Vol. 72, Issue 6
Allosteric Modulation of Muscarinic Acetylcholine Receptors
journal, September 2007
- Gregory, Karen; Sexton, Patrick; Christopoulos, Arthur
- Current Neuropharmacology, Vol. 5, Issue 3
Site-Directed Mutagenesis Reveals Two Epitopes Involved in the Subtype Selectivity of the Allosteric Interactions of Gallamine at Muscarinic Acetylcholine Receptors
journal, December 1999
- Gnagey, Ann L.; Seidenberg, Margaret; Ellis, John
- Molecular Pharmacology, Vol. 56, Issue 6
Molecular Basis for the Long Duration of Action and Kinetic Selectivity of Tiotropium for the Muscarinic M3 Receptor
journal, October 2013
- Tautermann, Christofer S.; Kiechle, Tobias; Seeliger, Daniel
- Journal of Medicinal Chemistry, Vol. 56, Issue 21
Activation and allosteric modulation of a muscarinic acetylcholine receptor
journal, November 2013
- Kruse, Andrew C.; Ring, Aaron M.; Manglik, Aashish
- Nature, Vol. 504, Issue 7478
Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders
journal, March 2009
- Conn, P. Jeffrey; Jones, Carrie K.; Lindsley, Craig W.
- Trends in Pharmacological Sciences, Vol. 30, Issue 3
Development of a Radioligand, [ 3 H]LY2119620, to Probe the Human M 2 and M 4 Muscarinic Receptor Allosteric Binding Sites
journal, May 2014
- Schober, Douglas A.; Croy, Carrie H.; Xiao, Hongling
- Molecular Pharmacology, Vol. 86, Issue 1
Characterization of the Novel Positive Allosteric Modulator, LY2119620, at the Muscarinic M 2 and M 4 Receptors
journal, May 2014
- Croy, Carrie H.; Schober, Douglas A.; Xiao, Hongling
- Molecular Pharmacology, Vol. 86, Issue 1
Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics
journal, May 2014
- Khoury, Etienne; Clément, Stéphanie; Laporte, Stéphane A.
- Frontiers in Endocrinology, Vol. 5
Multiple Residues in the Second Extracellular Loop Are Critical for M 3 Muscarinic Acetylcholine Receptor Activation
journal, January 2007
- Scarselli, Marco; Li, Bo; Kim, Soo-Kyung
- Journal of Biological Chemistry, Vol. 282, Issue 10
Critical Role for the Second Extracellular Loop in the Binding of Both Orthosteric and Allosteric G Protein-coupled Receptor Ligands
journal, June 2007
- Avlani, Vimesh A.; Gregory, Karen J.; Morton, Craig J.
- Journal of Biological Chemistry, Vol. 282, Issue 35
Evolutionarily Conserved Pathways of Energetic Connectivity in Protein Families
journal, October 1999
- Lockless, S. W.
- Science, Vol. 286, Issue 5438
PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations
journal, July 2004
- Dolinsky, T. J.; Nielsen, J. E.; McCammon, J. A.
- Nucleic Acids Research, Vol. 32, Issue Web Server, p. W665-W667
PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations
journal, May 2007
- Dolinsky, T. J.; Czodrowski, P.; Li, H.
- Nucleic Acids Research, Vol. 35, Issue Web Server
Electrostatics of nanosystems: Application to microtubules and the ribosome
journal, August 2001
- Baker, N. A.; Sept, D.; Joseph, S.
- Proceedings of the National Academy of Sciences, Vol. 98, Issue 18, p. 10037-10041
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Direct incorporation of experimental phase information in model refinement
journal, November 2004
- Skubák, Pavol; Murshudov, Garib N.; Pannu, Navraj S.
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: A historical perspective
journal, June 2009
- Guex, Nicolas; Peitsch, Manuel C.; Schwede, Torsten
- ELECTROPHORESIS, Vol. 30, Issue S1
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling
journal, November 2005
- Arnold, Konstantin; Bordoli, Lorenza; Kopp, Jürgen
- Bioinformatics, Vol. 22, Issue 2
SwissDock, a protein-small molecule docking web service based on EADock DSS
journal, May 2011
- Grosdidier, A.; Zoete, V.; Michielin, O.
- Nucleic Acids Research, Vol. 39, Issue suppl
New Insights into the Function of M 4 Muscarinic Acetylcholine Receptors Gained Using a Novel Allosteric Modulator and a DREADD (Designer Receptor Exclusively Activated by a Designer Drug)
journal, July 2008
- Nawaratne, Vindhya; Leach, Katie; Suratman, Nur
- Molecular Pharmacology, Vol. 74, Issue 4
ConSurf: Using Evolutionary Data to Raise Testable Hypotheses about Protein Function
journal, April 2013
- Celniker, Gershon; Nimrod, Guy; Ashkenazy, Haim
- Israel Journal of Chemistry, Vol. 53, Issue 3-4
ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids
journal, May 2010
- Ashkenazy, H.; Erez, E.; Martz, E.
- Nucleic Acids Research, Vol. 38, Issue Web Server
ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures
journal, July 2005
- Landau, M.; Mayrose, I.; Rosenberg, Y.
- Nucleic Acids Research, Vol. 33, Issue Web Server
ConSurf: Identification of Functional Regions in Proteins by Surface-Mapping of Phylogenetic Information
journal, January 2003
- Glaser, F.; Pupko, T.; Paz, I.
- Bioinformatics, Vol. 19, Issue 1
Clustal W and Clustal X version 2.0
journal, September 2007
- Larkin, M. A.; Blackshields, G.; Brown, N. P.
- Bioinformatics, Vol. 23, Issue 21, p. 2947-2948
Linking Crystallographic Model and Data Quality
journal, May 2012
- Karplus, P. A.; Diederichs, K.
- Science, Vol. 336, Issue 6084
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020
- Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
- JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
Computational studies of polyurethanases from Pseudomonas
journal, January 2021
- do Canto, Vanessa Petry; Thompson, Claudia Elizabeth; Netz, Paulo Augusto
- Journal of Molecular Modeling, Vol. 27, Issue 2
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019
- Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman
- Nature Communications, Vol. 10, Issue 1
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021
- Tillu, Vikas A.; Rae, James; Gao, Ya
- Nature Communications, Vol. 12, Issue 1
Rapid evolution of mammalian APLP1 as a synaptic adhesion molecule
journal, May 2021
- Onodera, Wataru; Asahi, Toru; Sawamura, Naoya
- Scientific Reports, Vol. 11, Issue 1
Direct incorporation of experimental phase information in model refinement
journal, August 2004
- Skubák, P.; Murshudov, G. N.; Pannu, N. S.
- Acta Crystallographica Section A Foundations of Crystallography, Vol. 60, Issue a1
Complete Genome Sequence of Clostridium botulinum CJ0611A1, a Type A(B) Isolate Associated with an International Outbreak of Botulism from Commercial Carrot Juice
journal, January 2021
- Harris, Richard; Dussault, Forest; Flint, Annika
- Microbiology Resource Announcements, Vol. 10, Issue 1
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
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- Agnetta, Luca; Kauk, Michael; Canizal, Maria Consuelo Alonso
- Angewandte Chemie International Edition, Vol. 56, Issue 25
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journal, October 2019
- Wifling, David; Pfleger, Christopher; Kaindl, Jonas
- Chemistry – A European Journal, Vol. 25, Issue 64
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journal, May 2019
- Grisoni, Francesca; Merk, Daniel; Friedrich, Lukas
- ChemMedChem, Vol. 14, Issue 12
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journal, July 2019
- Silva, Guilherme Martins; Barcelos, Mariana Pegrucci; Poiani, João Gabriel Curtolo
- ChemMedChem, Vol. 14, Issue 16
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journal, February 2018
- Agniswamy, Johnson; Reis, Renata A. G.; Wang, Yuan-Fang
- Proteins: Structure, Function, and Bioinformatics, Vol. 86, Issue 5
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book, January 2017
- Nasrallah, Chady; Lebon, Guillaume
- Structure and Function of GPCRs
Copper-mediated thiol potentiation and mutagenesis-guided modeling suggest a highly conserved copper-binding motif in human OR2M3
journal, August 2019
- Haag, Franziska; Ahmed, Lucky; Reiss, Krystle
- Cellular and Molecular Life Sciences, Vol. 77, Issue 11
Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects
journal, May 2019
- Menegatti, Ricardo; Carvalho, Flávio S.; Lião, Luciano M.
- Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 392, Issue 9
A benchmark study of loop modeling methods applied to G protein-coupled receptors
journal, May 2019
- Wink, Lee H.; Baker, Daniel L.; Cole, Judith A.
- Journal of Computer-Aided Molecular Design, Vol. 33, Issue 6
Three-dimensional descriptors for aminergic GPCRs: dependence on docking conformation and crystal structure
journal, November 2018
- Jastrzębski, Stanisław; Sieradzki, Igor; Leśniak, Damian
- Molecular Diversity, Vol. 23, Issue 3
A Perspective: Active Role of Lipids in Neurotransmitter Dynamics
journal, October 2019
- Postila, Pekka A.; Róg, Tomasz
- Molecular Neurobiology, Vol. 57, Issue 2
A kinetic view of GPCR allostery and biased agonism
journal, August 2017
- Lane, J. Robert; May, Lauren T.; Parton, Robert G.
- Nature Chemical Biology, Vol. 13, Issue 9
Discovery of new GPCR ligands to illuminate new biology
journal, October 2017
- Roth, Bryan L.; Irwin, John J.; Shoichet, Brian K.
- Nature Chemical Biology, Vol. 13, Issue 11
Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1
journal, January 2018
- Hori, Tetsuya; Okuno, Toshiaki; Hirata, Kunio
- Nature Chemical Biology, Vol. 14, Issue 3
The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors
journal, January 2018
- Joedicke, Lisa; Mao, Jiafei; Kuenze, Georg
- Nature Chemical Biology, Vol. 14, Issue 3
Development of an antibody fragment that stabilizes GPCR/G-protein complexes
journal, September 2018
- Maeda, Shoji; Koehl, Antoine; Matile, Hugues
- Nature Communications, Vol. 9, Issue 1
Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs
journal, July 2019
- Hollingsworth, Scott A.; Kelly, Brendan; Valant, Celine
- Nature Communications, Vol. 10, Issue 1
Minute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling
journal, October 2019
- Gupte, Tejas M.; Ritt, Michael; Dysthe, Matthew
- Nature Communications, Vol. 10, Issue 1
Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor
journal, November 2018
- Suno, Ryoji; Lee, Sangbae; Maeda, Shoji
- Nature Chemical Biology, Vol. 14, Issue 12
Molecular pharmacology of metabotropic receptors targeted by neuropsychiatric drugs
journal, July 2019
- Roth, Bryan L.
- Nature Structural & Molecular Biology, Vol. 26, Issue 7
Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors
journal, January 2017
- Jakubík, Jan; Randáková, Alena; Zimčík, Pavel
- Scientific Reports, Vol. 7, Issue 1
Exploring a new ligand binding site of G protein-coupled receptors
journal, January 2018
- Chan, H. C. Stephen; Wang, Jingjing; Palczewski, Krzysztof
- Chemical Science, Vol. 9, Issue 31
Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor
journal, September 2016
- Miao, Yinglong; Goldfeld, Dahlia Anne; Moo, Ee Von
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 38
Structure-based discovery of selective positive allosteric modulators of antagonists for the M 2 muscarinic acetylcholine receptor
journal, February 2018
- Korczynska, Magdalena; Clark, Mary J.; Valant, Celine
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 10
Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1
journal, March 2019
- Lückmann, Michael; Trauelsen, Mette; Bentsen, Marie A.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 14
Allosteric modulation of β-cell M 3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice
journal, August 2019
- Zhu, Lu; Rossi, Mario; Cohen, Amanda
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 37
Crystal structure of the M 5 muscarinic acetylcholine receptor
journal, November 2019
- Vuckovic, Ziva; Gentry, Patrick R.; Berizzi, Alice E.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 51
Backbone cyclization of analgesic conotoxin GeXIVA facilitates direct folding of the ribbon isomer
journal, August 2017
- Wu, Xiaosa; Huang, Yen-Hua; Kaas, Quentin
- Journal of Biological Chemistry, Vol. 292, Issue 41
Evidence of a M 1 -muscarinic GPCR homolog in unicellular eukaryotes: featuring Acanthamoeba spp bioinformatics 3D-modelling and experimentations
journal, September 2016
- Baig, Abdul Mannan; Ahmad, H. R.
- Journal of Receptors and Signal Transduction, Vol. 37, Issue 3
Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors
journal, September 2018
- Burger, Wessel A. C.; Sexton, Patrick M.; Christopoulos, Arthur
- Journal of General Physiology, Vol. 150, Issue 10
Crystal structure of the M 5 muscarinic acetylcholine receptor
journal, August 2019
- Vuckovic, Ziva; Gentry, Patrick R.; Berizzi, Alice E.
- Proceedings of the National Academy of Sciences
Allostery at opioid receptors: modulation with small molecule ligands
journal, June 2017
- Livingston, Kathryn E.; Traynor, John R.
- British Journal of Pharmacology, Vol. 175, Issue 14
Novel long-acting antagonists of muscarinic ACh receptors: Muscarinic long-acting antagonists
journal, April 2018
- Randáková, Alena; Rudajev, Vladimír; Doležal, Vladimír
- British Journal of Pharmacology, Vol. 175, Issue 10
Positive Allosteric Modulation of the Muscarinic M 1 Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior
journal, September 2016
- Choy, Kwok H. C.; Shackleford, David M.; Malone, Daniel T.
- Journal of Pharmacology and Experimental Therapeutics, Vol. 359, Issue 2
Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors
journal, December 2017
- Livingston, Kathryn E.; Stanczyk, M. Alexander; Burford, Neil T.
- Molecular Pharmacology, Vol. 93, Issue 2
Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes
journal, May 2019
- Maeda, Shoji; Qu, Qianhui; Robertson, Michael J.
- Science, Vol. 364, Issue 6440
Biased M 1 receptor–positive allosteric modulators reveal role of phospholipase D in M 1 -dependent rodent cortical plasticity
journal, December 2019
- Moran, Sean P.; Xiang, Zixiu; Doyle, Catherine A.
- Science Signaling, Vol. 12, Issue 610
Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands
journal, June 2019
- Schaller, David; Hagenow, Stefanie; Stark, Holger
- PLOS ONE, Vol. 14, Issue 6
Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration
journal, August 2016
- Ramsay, Rona R.; Majekova, Magdalena; Medina, Milagros
- Frontiers in Neuroscience, Vol. 10
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870
journal, November 2019
- Zhou, Ye; Cao, Can; He, Lingli
- eLife, Vol. 8
Backbone cyclization of analgesic conotoxin gexiva facilitates direct folding of the ribbon isomer
journal, February 2019
- Wu, Xiaosa; Huang, Yen-Hua; Kaas, Quentin
- Toxicon, Vol. 158
Discovery of new GPCR ligands to illuminate new biology
text, January 2017
- J. J., Irwin,; B. L., Roth,; B. K., Shoichet,
- Nature Publishing Group
Three-dimensional descriptors for aminergic GPCRs: dependence on docking conformation and crystal structure
journal, November 2018
- Jastrzębski, Stanisław; Sieradzki, Igor; Leśniak, Damian
- Molecular Diversity, Vol. 23, Issue 3
A Perspective: Active Role of Lipids in Neurotransmitter Dynamics
journal, October 2019
- Postila, Pekka A.; Róg, Tomasz
- Molecular Neurobiology, Vol. 57, Issue 2
Designer receptor technology for the treatment of epilepsy
journal, May 2019
- Lieb, Andreas; Weston, Mikail; Kullmann, Dimitri M.
- EBioMedicine, Vol. 43
Chemogenetic Approach Using Ni(II) Complex–Agonist Conjugates Allows Selective Activation of Class A G-Protein-Coupled Receptors
journal, August 2018
- Kubota, Ryou; Nomura, Wataru; Iwasaka, Takuma
- ACS Central Science, Vol. 4, Issue 9
Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs
journal, July 2019
- Hollingsworth, Scott A.; Kelly, Brendan; Valant, Celine
- Nature Communications, Vol. 10, Issue 1
Minute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling
journal, October 2019
- Gupte, Tejas M.; Ritt, Michael; Dysthe, Matthew
- Nature Communications, Vol. 10, Issue 1
Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor
journal, November 2018
- Suno, Ryoji; Lee, Sangbae; Maeda, Shoji
- Nature Chemical Biology, Vol. 14, Issue 12
Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness
journal, February 2019
- Xu, Pingxiang; Liu, Ying; Wang, Liyun
- Scientific Reports, Vol. 9, Issue 1
Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors
journal, January 2017
- Jakubík, Jan; Randáková, Alena; Zimčík, Pavel
- Scientific Reports, Vol. 7, Issue 1
Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1
journal, March 2019
- Lückmann, Michael; Trauelsen, Mette; Bentsen, Marie A.
- Proceedings of the National Academy of Sciences, Vol. 116, Issue 14
Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
journal, November 2018
- Liu, Hongtao; Hofmann, Josefa; Fish, Inbar
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 47
Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors
journal, September 2018
- Burger, Wessel A. C.; Sexton, Patrick M.; Christopoulos, Arthur
- Journal of General Physiology, Vol. 150, Issue 10
Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands
journal, June 2019
- Schaller, David; Hagenow, Stefanie; Stark, Holger
- PLOS ONE, Vol. 14, Issue 6
In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease
journal, June 2018
- Lemos, Agostinho; Melo, Rita; Preto, Antonio Jose
- Current Neuropharmacology, Vol. 16, Issue 6
Key Targets for Multi-Target Ligands Designed to Combat Neurodegeneration
journal, August 2016
- Ramsay, Rona R.; Majekova, Magdalena; Medina, Milagros
- Frontiers in Neuroscience, Vol. 10
Current Advances in Allosteric Modulation of Muscarinic Receptors
journal, February 2020
- Jakubik, Jan; El-Fakahany, Esam E.
- Biomolecules, Vol. 10, Issue 2
G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits
journal, February 2020
- Azam, Shofiul; Haque, Md. Ezazul; Jakaria, Md.
- Cells, Vol. 9, Issue 2
Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery
journal, August 2019
- Zou,
- International Journal of Molecular Sciences, Vol. 20, Issue 17
Antinociceptive Effect of the Essential Oil from Croton conduplicatus Kunth (Euphorbiaceae)
journal, May 2017
- de Oliveira Júnior, Raimundo; Ferraz, Christiane; Silva, Juliane
- Molecules, Vol. 22, Issue 6
Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction
journal, July 2018
- Sarapultsev, Alexey; Vassiliev, Pavel; Sarapultsev, Petr
- Molecules, Vol. 23, Issue 7
Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased M2R Affinity and Selectivity
text, January 2017
- She, Xueke; Pegoli, Andrea; Mayr, Judith
- Universität Regensburg
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870
journal, November 2019
- Zhou, Ye; Cao, Can; He, Lingli
- eLife, Vol. 8