8gf9

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of human TRPV1 in cNW11 nanodisc and POPC:POPE:POPG lipids

Structural highlights

8gf9 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.58Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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]^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hayes P, Meadows HJ, Gunthorpe MJ, Harries MH, Duckworth DM, Cairns W, Harrison DC, Clarke CE, Ellington K, Prinjha RK, Barton AJ, Medhurst AD, Smith GD, Topp S, Murdock P, Sanger GJ, Terrett J, Jenkins O, Benham CD, Randall AD, Gloger IS, Davis JB. Cloning and functional expression of a human orthologue of rat vanilloid receptor-1. Pain. 2000 Nov;88(2):205-15. doi: 10.1016/s0304-3959(00)00353-5. PMID:11050376 doi:http://dx.doi.org/10.1016/s0304-3959(00)00353-5
↑ McIntyre P, McLatchie LM, Chambers A, Phillips E, Clarke M, Savidge J, Toms C, Peacock M, Shah K, Winter J, Weerasakera N, Webb M, Rang HP, Bevan S, James IF. Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol. 2001 Mar;132(5):1084-94. doi: 10.1038/sj.bjp.0703918. PMID:11226139 doi:http://dx.doi.org/10.1038/sj.bjp.0703918
↑ Cortright DN, Crandall M, Sanchez JF, Zou T, Krause JE, White G. The tissue distribution and functional characterization of human VR1. Biochem Biophys Res Commun. 2001 Mar;281(5):1183-9. PMID:11243859 doi:http://dx.doi.org/10.1006/bbrc.2001.4482
↑ Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L, Egerton J, Charles KJ, Smart D, Randall AD, Anand P, Davis JB. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature. 2002 Jul 11;418(6894):186-90. doi: 10.1038/nature00894. Epub 2002 Jun 23. PMID:12077606 doi:http://dx.doi.org/10.1038/nature00894
↑ Neuberger A, Oda M, Nikolaev YA, Nadezhdin KD, Gracheva EO, Bagriantsev SN, Sobolevsky AI. Human TRPV1 structure and inhibition by the analgesic SB-366791. Nat Commun. 2023 Apr 28;14(1):2451. PMID:37117175 doi:10.1038/s41467-023-38162-9

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8gf9"

Categories: Homo sapiens | Large Structures | Nadezhdin KD | Neuberger A | Sobolevsky AI

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8gf9]] 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=8GF9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GF9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8IJ:(2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl+dioctadecanoate'>8IJ</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></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.58&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8IJ:(2R)-3-{[(R)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl+dioctadecanoate'>8IJ</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></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=8gf9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gf9 OCA], [https://pdbe.org/8gf9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gf9 RCSB], [https://www.ebi.ac.uk/pdbsum/8gf9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gf9 ProSAT]</span></td></tr>
 </table>
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 8gf9" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ion channels 3D structures|Ion channels 3D structures]]
 == References ==
 <references/>

8gf9

From Proteopedia

Current revision

Cryo-EM structure of human TRPV1 in cNW11 nanodisc and POPC:POPE:POPG lipids

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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