View source for 8gfa


==Cryo-EM structure of human TRPV1 in complex with the analgesic drug SB-366791==
<StructureSection load='8gfa' size='340' side='right'caption='[[8gfa]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8gfa]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GFA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GFA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.29&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DU0:2-[2-[(1~{S},2~{S},4~{S},5~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5,7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2-oxane]-16-yl]oxyethyl]propane-1,3-diol'>DU0</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene>, <scene name='pdbligand=ZEI:(2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)prop-2-enamide'>ZEI</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8gfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gfa OCA], [https://pdbe.org/8gfa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gfa RCSB], [https://www.ebi.ac.uk/pdbsum/8gfa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gfa ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TRPV1_HUMAN TRPV1_HUMAN] Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis.[UniProtKB:O35433]<ref>PMID:11050376</ref> <ref>PMID:11226139</ref> <ref>PMID:11243859</ref> <ref>PMID:12077606</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

Human TRPV1 structure and inhibition by the analgesic SB-366791.,Neuberger A, Oda M, Nikolaev YA, Nadezhdin KD, Gracheva EO, Bagriantsev SN, Sobolevsky AI Nat Commun. 2023 Apr 28;14(1):2451. doi: 10.1038/s41467-023-38162-9. PMID:37117175<ref>PMID:37117175</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8gfa" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Nadezhdin KD]]
[[Category: Neuberger A]]
[[Category: Sobolevsky AI]]