Human TRPV1 structure and inhibition by the analgesic SB-366791

Neuberger, Arthur; Oda, Mai; Nikolaev, Yury A.; Nadezhdin, Kirill D.; Gracheva, Elena O.; Bagriantsev, Sviatoslav N.; Sobolevsky, Alexander I.

doi:10.1038/s41467-023-38162-9

Human TRPV1 structure and inhibition by the analgesic SB-366791

Journal Article · Fri Apr 28 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-38162-9· OSTI ID:2425440

^[1]; Oda, Mai ^[2]; Nikolaev, Yury A. ^[2]; ^[1]; Gracheva, Elena O. ^[3]; ^[2]; ^[1]

Columbia Univ., New York, NY (United States)
Yale Univ., New Haven, CT (United States)
Yale Univ., New Haven, CT (United States); Yale Univ., New Haven, CT (United States). Kavli Institute for Neuroscience

Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). Laboratory for BioMolecular Structure (LBMS)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: SC0012704

OSTI ID:: 2425440

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (56)

UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists Aghazadeh Tabrizi, Mojgan; Baraldi, Pier Giovanni; Baraldi, Stefania Medicinal Research Reviews, Vol. 37, Issue 4 https://doi.org/10.1002/med.21427	journal	December 2016
UCSF ChimeraX : Structure visualization for researchers, educators, and developers Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Protein Science, Vol. 30, Issue 1 https://doi.org/10.1002/pro.3943	journal	October 2020
Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist Gunthorpe, M. J.; Rami, H. K.; Jerman, J. C. Neuropharmacology, Vol. 46, Issue 1 https://doi.org/10.1016/S0028-3908(03)00305-8	journal	January 2004
HOLE: A program for the analysis of the pore dimensions of ion channel structural models Smart, Oliver S.; Neduvelil, Joseph G.; Wang, Xiaonan Journal of Molecular Graphics, Vol. 14, Issue 6 https://doi.org/10.1016/S0263-7855(97)00009-X	journal	December 1996
Cellular and Molecular Mechanisms of Pain Basbaum, Allan I.; Bautista, Diana M.; Scherrer, Grégory Cell, Vol. 139, Issue 2 https://doi.org/10.1016/j.cell.2009.09.028	journal	October 2009
Structural snapshots of TRPV1 reveal mechanism of polymodal functionality Zhang, Kaihua; Julius, David; Cheng, Yifan Cell, Vol. 184, Issue 20 https://doi.org/10.1016/j.cell.2021.08.012	journal	September 2021
Addiction to opioids in chronic pain patients: A literature review Højsted, Jette; Sjøgren, Per European Journal of Pain, Vol. 11, Issue 5 https://doi.org/10.1016/j.ejpain.2006.08.004	journal	July 2007
TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation Lappin, Sarah C.; Randall, Andrew D.; Gunthorpe, Martin J. European Journal of Pharmacology, Vol. 540, Issue 1-3 https://doi.org/10.1016/j.ejphar.2006.04.046	journal	July 2006
RELION: Implementation of a Bayesian approach to cryo-EM structure determination Scheres, Sjors H. W. Journal of Structural Biology, Vol. 180, Issue 3, p. 519-530 https://doi.org/10.1016/j.jsb.2012.09.006	journal	December 2012
Synergistic antinociceptive effect of a calcium channel blocker and a TRPV1 blocker in an acute pain model in mice Palhares, Manuella R.; Silva, Juliana F.; Rezende, Marcio Junior S. Life Sciences, Vol. 182 https://doi.org/10.1016/j.lfs.2017.06.018	journal	August 2017
Effects of the novel TRPV1 receptor antagonist SB366791 in vitro and in vivo in the rat Varga, Angelika; Németh, József; Szabó, Árpád Neuroscience Letters, Vol. 385, Issue 2 https://doi.org/10.1016/j.neulet.2005.05.015	journal	September 2005
The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior Fogaça, Manoela V.; Aguiar, Daniele C.; Moreira, Fabrício A. Neuropharmacology, Vol. 63, Issue 2 https://doi.org/10.1016/j.neuropharm.2012.03.007	journal	August 2012
Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within distinct subpopulations of dorsal root ganglion neurons Niiyama, Y.; Kawamata, T.; Yamamoto, J. Neuroscience, Vol. 148, Issue 2 https://doi.org/10.1016/j.neuroscience.2007.05.049	journal	August 2007
SerialEM: A Program for Automated Tilt Series Acquisition on Tecnai Microscopes Using Prediction of Specimen Position Mastronarde, David N. Microscopy and Microanalysis, Vol. 9, Issue S02 https://doi.org/10.1017/S1431927603445911	journal	July 2003
A capsaicin-receptor homologue with a high threshold for noxious heat Caterina, Michael J.; Rosen, Tobias A.; Tominaga, Makoto Nature, Vol. 398, Issue 6726 https://doi.org/10.1038/18906	journal	April 1999
The capsaicin receptor: a heat-activated ion channel in the pain pathway Caterina, Michael J.; Schumacher, Mark A.; Tominaga, Makoto Nature, Vol. 389, Issue 6653 https://doi.org/10.1038/39807	journal	October 1997
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment Long, Stephen B.; Tao, Xiao; Campbell, Ernest B. Nature, Vol. 450, Issue 7168 https://doi.org/10.1038/nature06265	journal	November 2007
Structure of the TRPV1 ion channel determined by electron cryo-microscopy Liao, Maofu; Cao, Erhu; Julius, David Nature, Vol. 504, Issue 7478 https://doi.org/10.1038/nature12822	journal	December 2013
TRPV1 structures in distinct conformations reveal activation mechanisms Cao, Erhu; Liao, Maofu; Cheng, Yifan Nature, Vol. 504, Issue 7478 https://doi.org/10.1038/nature12823	journal	December 2013
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action Gao, Yuan; Cao, Erhu; Julius, David Nature, Vol. 534, Issue 7607 https://doi.org/10.1038/nature17964	journal	May 2016
Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel Yang, Fan; Xiao, Xian; Cheng, Wei Nature Chemical Biology, Vol. 11, Issue 7 https://doi.org/10.1038/nchembio.1835	journal	June 2015
Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch Morales-Lázaro, Sara L.; Llorente, Itzel; Sierra-Ramírez, Félix Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms13092	journal	October 2016
TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice Marrone, Maria Cristina; Morabito, Annunziato; Giustizieri, Michela Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms15292	journal	May 2017
Covalently circularized nanodiscs for studying membrane proteins and viral entry Nasr, Mahmoud L.; Baptista, Diego; Strauss, Mike Nature Methods, Vol. 14, Issue 1 https://doi.org/10.1038/nmeth.4079	journal	November 2016
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy Zheng, Shawn Q.; Palovcak, Eugene; Armache, Jean-Paul Nature Methods, Vol. 14, Issue 4 https://doi.org/10.1038/nmeth.4193	journal	February 2017
Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain Grandl, Jörg; Kim, Sung Eun; Uzzell, Valerie Nature Neuroscience, Vol. 13, Issue 6 https://doi.org/10.1038/nn.2552	journal	April 2010
Opposing Roles for Cannabinoid Receptor Type-1 (CB1) and Transient Receptor Potential Vanilloid Type-1 Channel (TRPV1) on the Modulation of Panic-Like Responses in Rats Casarotto, Plínio C.; Terzian, Ana Luisa B.; Aguiar, Daniele C. Neuropsychopharmacology, Vol. 37, Issue 2 https://doi.org/10.1038/npp.2011.207	journal	September 2011
Screening and large-scale expression of membrane proteins in mammalian cells for structural studies Goehring, April; Lee, Chia-Hsueh; Wang, Kevin H. Nature Protocols, Vol. 9, Issue 11 https://doi.org/10.1038/nprot.2014.173	journal	October 2014
Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB Singh, Appu K.; Saotome, Kei; McGoldrick, Luke L. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-04828-y	journal	June 2018
Extracellular cap domain is an essential component of the TRPV1 gating mechanism Nadezhdin, Kirill D.; Neuberger, Arthur; Nikolaev, Yury A. Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-22507-3	journal	April 2021
Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole Neuberger, Arthur; Nadezhdin, Kirill D.; Sobolevsky, Alexander I. Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-26608-x	journal	November 2021
Structural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine Neuberger, Arthur; Nadezhdin, Kirill D.; Sobolevsky, Alexander I. Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-30537-8	journal	May 2022
Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis Kwon, Do Hoon; Zhang, Feng; Fedor, Justin G. Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-30602-2	journal	May 2022
Structure and gating mechanism of the transient receptor potential channel TRPV3 Singh, Appu K.; McGoldrick, Luke L.; Sobolevsky, Alexander I. Nature Structural & Molecular Biology, Vol. 25, Issue 9 https://doi.org/10.1038/s41594-018-0108-7	journal	August 2018
Structural basis of temperature sensation by the TRP channel TRPV3 Singh, Appu K.; McGoldrick, Luke L.; Demirkhanyan, Lusine Nature Structural & Molecular Biology, Vol. 26, Issue 11 https://doi.org/10.1038/s41594-019-0318-7	journal	October 2019
Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel Nadezhdin, Kirill D.; Neuberger, Arthur; Trofimov, Yuri A. Nature Structural & Molecular Biology, Vol. 28, Issue 7 https://doi.org/10.1038/s41594-021-00615-4	journal	July 2021
Heat-dependent opening of TRPV1 in the presence of capsaicin Kwon, Do Hoon; Zhang, Feng; Suo, Yang Nature Structural & Molecular Biology, Vol. 28, Issue 7 https://doi.org/10.1038/s41594-021-00616-3	journal	July 2021
Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels Laursen, Willem J.; Schneider, Eve R.; Merriman, Dana K. Proceedings of the National Academy of Sciences, Vol. 113, Issue 40 https://doi.org/10.1073/pnas.1604269113	journal	September 2016
TRPV1 pore turret dictates distinct DkTx and capsaicin gating Geron, Matan; Kumar, Rakesh; Zhou, Wenchang Proceedings of the National Academy of Sciences, Vol. 115, Issue 50 https://doi.org/10.1073/pnas.1809662115	journal	November 2018
Conserved Residues within the Putative S4–S5 Region Serve Distinct Functions among Thermosensitive Vanilloid Transient Receptor Potential (TRPV) Channels Boukalova, Stepana; Marsakova, Lenka; Teisinger, Jan Journal of Biological Chemistry, Vol. 285, Issue 53 https://doi.org/10.1074/jbc.M110.145466	journal	December 2010
SB366791, a TRPV1 antagonist, potentiates analgesic effects of systemic morphine in a murine model of bone cancer pain † Niiyama, Y.; Kawamata, T.; Yamamoto, J. British Journal of Anaesthesia, Vol. 102, Issue 2 https://doi.org/10.1093/bja/aen347	journal	February 2009
TRPV1 blockers as potential new treatments for psychiatric disorders Iglesias, Lia P.; Aguiar, Daniele C.; Moreira, Fabrício A. Behavioural Pharmacology, Vol. 33, Issue 1 https://doi.org/10.1097/FBP.0000000000000603	journal	October 2020
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
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
Impairment of opiate‐mediated behaviors by the selective TRPV1 antagonist SB366791 Ma, Shi‐Xun; Kwon, Seung‐Hwan; Seo, Jee‐Yeon Addiction Biology, Vol. 22, Issue 6 https://doi.org/10.1111/adb.12460	journal	October 2016
Transient receptor potential (TRP) channels: a clinical perspective Kaneko, Yosuke; Szallasi, Arpad British Journal of Pharmacology, Vol. 171, Issue 10 https://doi.org/10.1111/bph.12414	journal	April 2014
Structure of an agonist-bound ionotropic glutamate receptor Yelshanskaya, M. V.; Li, M.; Sobolevsky, A. I. Science, Vol. 345, Issue 6200 https://doi.org/10.1126/science.1256508	journal	August 2014
TRP Channels and Pain Julius, David Annual Review of Cell and Developmental Biology, Vol. 29, Issue 1 https://doi.org/10.1146/annurev-cellbio-101011-155833	journal	October 2013
TRP Channel Cooperation for Nociception: Therapeutic Opportunities Bamps, Dorien; Vriens, Joris; de Hoon, Jan Annual Review of Pharmacology and Toxicology, Vol. 61, Issue 1 https://doi.org/10.1146/annurev-pharmtox-010919-023238	journal	January 2021
TRP channels as emerging targets for pain therapeutics Broad, Lisa M.; Mogg, Adrian J.; Beattie, Ruth E. Expert Opinion on Therapeutic Targets, Vol. 13, Issue 1 https://doi.org/10.1517/14728220802616620	journal	December 2008
Reduced Anxiety, Conditioned Fear, and Hippocampal Long-Term Potentiation in Transient Receptor Potential Vanilloid Type 1 Receptor-Deficient Mice Marsch, Rudolph; Foeller, Elisabeth; Rammes, Gerhard The Journal of Neuroscience, Vol. 27, Issue 4 https://doi.org/10.1523/JNEUROSCI.3303-06.2007	journal	January 2007
Structural mechanism of TRPV3 channel inhibition by the plant‐derived coumarin osthole Neuberger, Arthur; Nadezhdin, Kirill D.; Zakharian, Eleonora EMBO reports, Vol. 22, Issue 11 https://doi.org/10.15252/embr.202153233	journal	September 2021
Ligand-Binding Sites in Vanilloid-Subtype TRP Channels Yelshanskaya, Maria V.; Sobolevsky, Alexander I. Frontiers in Pharmacology, Vol. 13 https://doi.org/10.3389/fphar.2022.900623	journal	May 2022
Structure-based characterization of novel TRPV5 inhibitors Hughes, Taylor ET; Del Rosario, John Smith; Kapoor, Abhijeet eLife, Vol. 8 https://doi.org/10.7554/eLife.49572	journal	October 2019

Similar Records

A single TRPV1 amino acid controls species sensitivity to capsaicin

Journal Article · Fri May 15 00:00:00 EDT 2020 · Scientific Reports · OSTI ID:1631670

Distinct properties of Ca²⁺-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel

Journal Article · Thu Nov 01 00:00:00 EDT 2012 · Journal of General Physiology · OSTI ID:1054358

Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor

Journal Article · Tue Apr 11 00:00:00 EDT 2023 · International Journal of Molecular Sciences (Online) · OSTI ID:2425825

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
cryoelectron microscopy
transient receptor potential channels

Human TRPV1 structure and inhibition by the analgesic SB-366791

Citation Formats

References (56)

Similar Records

Related Subjects