Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist

Zhang, Chen; Zhang, Tuo; Zou, Juan; Miller, Cassandra Lynn; Gorkhali, Rakshya; Yang, Jeong-Yeh; Schilmiller, Anthony; Wang, Shuo; Huang, Kenneth; Brown, Edward M.; Moremen, Kelley W.; Hu, Jian; Yang, Jenny J.

doi:10.1126/sciadv.1600241

Title: Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist

Journal Article · Fri May 27 00:00:00 EDT 2016 · Science Advances

DOI:https://doi.org/10.1126/sciadv.1600241· OSTI ID:1256347

Zhang, Chen ^[1]; Zhang, Tuo ^[2]; Zou, Juan ^[1];

^[1]; Gorkhali, Rakshya ^[1];

^[3];

^[2]; Wang, Shuo ^[3];

^[1]; Brown, Edward M. ^[4];

^[3]; Hu, Jian ^[2]; Yang, Jenny J. ^[1]

Georgia State Univ., Atlanta, GA (United States)
Michigan State Univ., East Lansing, MI (United States)
Univ. of Georgia, Athens, GA (United States)
Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (United States)

Ca²⁺-sensing receptors (CaSRs) modulate calcium and magnesium homeostasis and many (patho)physiological processes by responding to extracellular stimuli, including divalent cations and amino acids. We report the first crystal structure of the extracellular domain (ECD) of human CaSR bound with Mg²⁺and a tryptophan derivative ligand at 2.1 Å. The structure reveals key determinants for cooperative activation by metal ions and aromatic amino acids. The unexpected tryptophan derivative was bound in the hinge region between two globular ECD subdomains, and represents a novel high-affinity co-agonist of CaSR. The dissection of structure-function relations by mutagenesis, biochemical, and functional studies provides insights into the molecular basis of human diseases arising from CaSR mutations. The data also provide a novel paradigm for understanding the mechanism of CaSR-mediated signaling that is likely shared by the other family C GPCR [G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor] members and can facilitate the development of novel CaSR-based therapeutics.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); Georgia Research Alliance

Grant/Contract Number:: GM081749; EB007268; GM115373

OSTI ID:: 1256347

Journal Information:: Science Advances, Vol. 2, Issue 5; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 81 works

Citation information provided by
Web of Science

References (40)

Extracellular calcium sensing and signalling Hofer, Aldebaran M.; Brown, Edward M. Nature Reviews Molecular Cell Biology, Vol. 4, Issue 7 https://doi.org/10.1038/nrm1154	journal	July 2003
Identification and Dissection of Ca ²⁺ -binding Sites in the Extracellular Domain of Ca ²⁺ -sensing Receptor Huang, Yun; Zhou, Yubin; Yang, Wei Journal of Biological Chemistry, Vol. 282, Issue 26 https://doi.org/10.1074/jbc.m701096200	journal	May 2007
Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites Hannan, F. M.; Nesbit, M. A.; Zhang, C. Human Molecular Genetics, Vol. 21, Issue 12 https://doi.org/10.1093/hmg/dds105	journal	March 2012
Cell signaling, beyond cytosolic calcium in eukaryotes Permyakov, E.; Kretsinger, R. Journal of Inorganic Biochemistry, Vol. 103, Issue 1 https://doi.org/10.1016/j.jinorgbio.2008.09.006	journal	January 2009
Agonist-Driven Maturation and Plasma Membrane Insertion of Calcium-Sensing Receptors Dynamically Control Signal Amplitude Grant, M. P.; Stepanchick, A.; Cavanaugh, A. Science Signaling, Vol. 4, Issue 200 https://doi.org/10.1126/scisignal.2002208	journal	November 2011
Direct Determination of Multiple Ligand Interactions with the Extracellular Domain of the Calcium-sensing Receptor Zhang, Chen; Zhuo, You; Moniz, Heather A. Journal of Biological Chemistry, Vol. 289, Issue 48 https://doi.org/10.1074/jbc.m114.604652	journal	October 2014
CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia Pidasheva, Svetlana; D'Souza-Li, Lilia; Canaff, Lucie Human Mutation, Vol. 24, Issue 2 https://doi.org/10.1002/humu.20067	journal	January 2004
CaSR-mediated interactions between calcium and magnesium homeostasis in mice Quinn, Stephen J.; Thomsen, Alex R. B.; Egbuna, Ogo American Journal of Physiology-Endocrinology and Metabolism, Vol. 304, Issue 7 https://doi.org/10.1152/ajpendo.00557.2012	journal	April 2013
Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism Hannan, Fadil M.; Thakker, Rajesh V. Best Practice & Research Clinical Endocrinology & Metabolism, Vol. 27, Issue 3 https://doi.org/10.1016/j.beem.2013.04.007	journal	June 2013
Structural analysis, identification, and design of calcium-binding sites in proteins Yang, Wei; Lee, Hsiau-Wei; Hellinga, Homme Proteins: Structure, Function, and Genetics, Vol. 47, Issue 3 https://doi.org/10.1002/prot.10093	journal	April 2002
Extracellular Ca2+-sensing receptors—an overview Chang, Wenhan; Shoback, Dolores Cell Calcium, Vol. 35, Issue 3 https://doi.org/10.1016/j.ceca.2003.10.012	journal	March 2004
Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1 S ,2 S ,5 R ,6 S -2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures Monn, James A.; Prieto, Lourdes; Taboada, Lorena Journal of Medicinal Chemistry, Vol. 58, Issue 4 https://doi.org/10.1021/jm501612y	journal	February 2015
pH Sensing by the Calcium-sensing Receptor Quinn, Stephen J.; Bai, Mei; Brown, Edward M. Journal of Biological Chemistry, Vol. 279, Issue 36 https://doi.org/10.1074/jbc.m404520200	journal	June 2004
Structural mechanism of ligand activation in human GABAB receptor Geng, Yong; Bush, Martin; Mosyak, Lidia Nature, Vol. 504, Issue 7479 https://doi.org/10.1038/nature12725	journal	December 2013
Identification of the Cysteine Residues in the Amino-terminal Extracellular Domain of the Human Ca2+ Receptor Critical for Dimerization Ray, Kausik; Hauschild, Benjamin C.; Steinbach, Peter J. Journal of Biological Chemistry, Vol. 274, Issue 39 https://doi.org/10.1074/jbc.274.39.27642	journal	September 1999
The Calcium-Sensing Receptor: A Molecular Perspective Magno, Aaron L.; Ward, Bryan K.; Ratajczak, Thomas Endocrine Reviews, Vol. 32, Issue 1 https://doi.org/10.1210/er.2009-0043	journal	February 2011
Negative Cooperativity of Glutamate Binding in the Dimeric Metabotropic Glutamate Receptor Subtype 1 Suzuki, Yoshikazu; Moriyoshi, Eiko; Tsuchiya, Daisuke Journal of Biological Chemistry, Vol. 279, Issue 34 https://doi.org/10.1074/jbc.m404831200	journal	June 2004
Extracellular calcium-sensing receptor: Implications for calcium and magnesium handling in the kidney Hebert, Steven C. Kidney International, Vol. 50, Issue 6 https://doi.org/10.1038/ki.1996.539	journal	December 1996
Direct determination of silicon in powdered aluminium oxide by use of slurry sampling with in situ fusion graphite-furnace atomic-absorption spectrometry Minami, H.; Yoshida, Tomomi; Okutsu, Kentaro Fresenius' Journal of Analytical Chemistry, Vol. 370, Issue 7 https://doi.org/10.1007/s002160100901	journal	August 2001
Structural Basis for a Ca2+-Sensing Function of the Metabotropic Glutamate Receptors Kubo, Y. Science, Vol. 279, Issue 5357 https://doi.org/10.1126/science.279.5357.1722	journal	March 1998
Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid Brown, Edward M.; Gamba, Gerardo; Riccardi, Daniela Nature, Vol. 366, Issue 6455 https://doi.org/10.1038/366575a0	journal	December 1993
Delineating a Ca ²⁺ Binding Pocket within the Venus Flytrap Module of the Human Calcium-sensing Receptor Silve, Caroline; Petrel, Christophe; Leroy, Christine Journal of Biological Chemistry, Vol. 280, Issue 45 https://doi.org/10.1074/jbc.m506263200	journal	September 2005
Multiple Ca ²⁺ -Binding Sites in the Extracellular Domain of the Ca ²⁺ -Sensing Receptor Corresponding to Cooperative Ca ²⁺ Response ^† Huang, Yun; Zhou, Yubin; Castiblanco, Adriana Biochemistry, Vol. 48, Issue 2 https://doi.org/10.1021/bi8014604	journal	January 2009
Structure and function of the extracellular calcium-sensing receptor (Review). Bai, M. International Journal of Molecular Medicine https://doi.org/10.3892/ijmm.4.2.115	journal	August 1999
Extracellular Calcium Sensing and Extracellular Calcium Signaling Brown, Edward M.; MacLeod, R. John Physiological Reviews, Vol. 81, Issue 1 https://doi.org/10.1152/physrev.2001.81.1.239	journal	January 2001
Sensing mechanisms involved in Ca2+ and Mg2+ homeostasis Ferrè, Silvia; Hoenderop, Joost G. J.; Bindels, René J. M. Kidney International, Vol. 82, Issue 11 https://doi.org/10.1038/ki.2012.179	journal	December 2012
l -Tryptophan Reacts with Naturally Occurring and Food-Occurring Phenolic Aldehydes To Give Phenolic Tetrahydro-β-carboline Alkaloids: Activity as Antioxidants and Free Radical Scavengers Herraiz, Tomas; Galisteo, Juan; Chamorro, Cristina Journal of Agricultural and Food Chemistry, Vol. 51, Issue 8 https://doi.org/10.1021/jf0210066	journal	April 2003
Calcimimetic and Calcilytic Drugs: Feats, Flops, and Futures Nemeth, E. F.; Goodman, W. G. Calcified Tissue International, Vol. 98, Issue 4 https://doi.org/10.1007/s00223-015-0052-z	journal	August 2015
Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+ Tsuchiya, D.; Kunishima, N.; Kamiya, N. Proceedings of the National Academy of Sciences, Vol. 99, Issue 5 https://doi.org/10.1073/pnas.052708599	journal	February 2002
A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism Ho, Chrystal; Conner, David A.; Pollak, Martin R. Nature Genetics, Vol. 11, Issue 4 https://doi.org/10.1038/ng1295-389	journal	December 1995
Identification of an l-Phenylalanine Binding Site Enhancing the Cooperative Responses of the Calcium-sensing Receptor to Calcium Zhang, Chen; Huang, Yun; Jiang, Yusheng Journal of Biological Chemistry, Vol. 289, Issue 8 https://doi.org/10.1074/jbc.m113.537357	journal	January 2014
Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor Kunishima, Naoki; Shimada, Yoshimi; Tsuji, Yuji Nature, Vol. 407, Issue 6807 https://doi.org/10.1038/35039564	journal	October 2000
Extracellular Mg2+- and Ca2+-sensing in mouse distal convoluted tubule cells Bapty, Brian W.; Dai, Long-jun; Ritchie, Gordon Kidney International, Vol. 53, Issue 3 https://doi.org/10.1046/j.1523-1755.1998.00790.x	journal	March 1998
L-Amino acid sensing by the extracellular Ca2+-sensing receptor Conigrave, A. D.; Quinn, S. J.; Brown, E. M. Proceedings of the National Academy of Sciences, Vol. 97, Issue 9 https://doi.org/10.1073/pnas.97.9.4814	journal	April 2000
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Enzymatic Basis for N -Glycan Sialylation : STRUCTURE OF RAT α2,6-SIALYLTRANSFERASE (ST6GAL1) REVEALS CONSERVED AND UNIQUE FEATURES FOR GLYCAN SIALYLATION Meng, Lu; Forouhar, Farhad; Thieker, David Journal of Biological Chemistry, Vol. 288, Issue 48 https://doi.org/10.1074/jbc.M113.519041	journal	October 2013
NMRPipe: A multidimensional spectral processing system based on UNIX pipes Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW. Journal of Biomolecular NMR, Vol. 6, Issue 3 https://doi.org/10.1007/BF00197809	journal	November 1995
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011

Cited By (21)

Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits Park, Jihye; Selvam, Balaji; Sanematsu, Keisuke Journal of Biological Chemistry, Vol. 294, Issue 13 https://doi.org/10.1074/jbc.ra118.006173	journal	February 2019
Calcium-sensing receptor residues with loss- and gain-of-function mutations are located in regions of conformational change and cause signalling bias Gorvin, Caroline M.; Frost, Morten; Malinauskas, Tomas Human Molecular Genetics, Vol. 27, Issue 21 https://doi.org/10.1093/hmg/ddy263	journal	July 2018
Recent advances in understanding the extracellular calcium-sensing receptor Colella, Matilde; Gerbino, Andrea; Hofer, Aldebaran M. F1000Research, Vol. 5 https://doi.org/10.12688/f1000research.8963.1	journal	October 2016
Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism Cavaco, Branca M.; Canaff, Lucie; Nolin-Lapalme, Alexis The Journal of Clinical Endocrinology & Metabolism, Vol. 103, Issue 8 https://doi.org/10.1210/jc.2017-02407	journal	May 2018
Magnesium Replacement to Protect Cardiovascular and Kidney Damage? Lack of Prospective Clinical Trials Muñoz-Castañeda, Juan; Pendón-Ruiz de Mier, María; Rodríguez, Mariano International Journal of Molecular Sciences, Vol. 19, Issue 3 https://doi.org/10.3390/ijms19030664	journal	February 2018
Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis Hannan, Fadil M.; Babinsky, Valerie N.; Thakker, Rajesh V. Journal of Molecular Endocrinology, Vol. 57, Issue 3 https://doi.org/10.1530/jme-16-0124	journal	October 2016
Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion Centeno, Patricia P.; Herberger, Amanda; Mun, Hee-Chang Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-12399-9	journal	October 2019
PredCSO: an ensemble method for the prediction of S-sulfenylation sites in proteins Deng, Lei; Xu, Xiaojie; Liu, Hui Molecular Omics, Vol. 14, Issue 4 https://doi.org/10.1039/c8mo00089a	journal	January 2018
Identification of Serine-875 as an Inhibitory Phosphorylation Site in the Calcium-Sensing Receptor Binmahfouz, Lenah S.; Centeno, Patricia P.; Conigrave, Arthur D. Molecular Pharmacology, Vol. 96, Issue 2 https://doi.org/10.1124/mol.119.116178	journal	June 2019
Calcium-Sensing Receptor Internalization Is β -Arrestin–Dependent and Modulated by Allosteric Ligands Mos, Iris; Jacobsen, Stine E.; Foster, Simon R. Molecular Pharmacology, Vol. 96, Issue 4 https://doi.org/10.1124/mol.119.116772	journal	August 2019
Structural insights into G-protein-coupled receptor allostery Thal, David M.; Glukhova, Alisa; Sexton, Patrick M. Nature, Vol. 559, Issue 7712 https://doi.org/10.1038/s41586-018-0259-z	journal	July 2018
The Calcium-Sensing Receptor and the Parathyroid: Past, Present, Future Conigrave, Arthur D. Frontiers in Physiology, Vol. 7 https://doi.org/10.3389/fphys.2016.00563	journal	December 2016
Editorial: Physiology and Pathophysiology of the Extracellular Calcium-Sensing Receptor Kallay, Enikö Frontiers in Physiology, Vol. 9 https://doi.org/10.3389/fphys.2018.00413	journal	May 2018
The Nervous System Relevance of the Calcium Sensing Receptor in Health and Disease Giudice, Maria Lo; Mihalik, Balázs; Dinnyés, András Molecules, Vol. 24, Issue 14 https://doi.org/10.3390/molecules24142546	journal	July 2019
The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases Das, Souvik; Clézardin, Philippe; Kamel, Said Frontiers in Oncology, Vol. 10 https://doi.org/10.3389/fonc.2020.00069	journal	February 2020
Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2+ Zou, Juan; Jiang, Jason; Yang, Jenny International Journal of Molecular Sciences, Vol. 18, Issue 3 https://doi.org/10.3390/ijms18030672	journal	March 2017
Structural basis for perception of diverse chemical substances by T1r taste receptors Nuemket, Nipawan; Yasui, Norihisa; Kusakabe, Yuko Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms15530	journal	May 2017
Expression system for structural and functional studies of human glycosylation enzymes Moremen, Kelley W.; Ramiah, Annapoorani; Stuart, Melissa Nature Chemical Biology, Vol. 14, Issue 2 https://doi.org/10.1038/nchembio.2539	journal	December 2017
Investigating the molecular mechanism of positive and negative allosteric modulators in the calcium-sensing receptor dimer Jacobsen, Stine Engesgaard; Gether, Ulrik; Bräuner-Osborne, Hans Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep46355	journal	April 2017
Renal Ca2+ and Water Handling in Response to Calcium Sensing Receptor Signaling: Physiopathological Aspects and Role of CaSR-Regulated microRNAs Ranieri, Marianna International Journal of Molecular Sciences, Vol. 20, Issue 21 https://doi.org/10.3390/ijms20215341	journal	October 2019
Microporous polysaccharide multilayer coated BCP composite scaffolds with immobilised calcitriol promote osteoporotic bone regeneration both in vitro and in vivo Tang, Qian; Hu, Zhichao; Jin, Haiming Theranostics, Vol. 9, Issue 4 https://doi.org/10.7150/thno.29566	journal	January 2019

Similar Records

Structural mechanism of ligand activation in human calcium-sensing receptor

Journal Article · Tue Jul 19 00:00:00 EDT 2016 · eLife · OSTI ID:1256347

Geng, Yong; Mosyak, Lidia; Kurinov, Igor; +17 more

The 2.6 Angstrom Crystal Structure of a Human A[subscript 2A] Adenosine Receptor Bound to an Antagonist

Journal Article · Thu Jan 15 00:00:00 EST 2009 · Science · OSTI ID:1256347

Jaakola, Veli-Pekka; Griffith, Mark T; Hanson, Michael A; +5 more

Unexpected role of a conserved domain in the first extracellular loop in G protein-coupled receptor trafficking

Journal Article · Sat Sep 15 00:00:00 EDT 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1256347

Rizzo, Michael J.; Evans, John P.; Burt, Morgan; +1 more

Related Subjects

Calcium Sensing Receptor
TNCA
Crystal Structure
Mg2+
L-Phe
Binding Affinity
EC50

Title: Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist

Citation Formats

References (40)

Cited By (21)

Similar Records

Related Subjects