7rqw
From Proteopedia
Cryo-EM structure of the full-length TRPV1 with RTx at 4 degrees Celsius, in an open state, class III
Structural highlights
FunctionTRPV1_RAT Receptor-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. May be 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Publication Abstract from PubMedSingle particle cryo-EM often yields multiple protein conformations within a single dataset, but experimentally deducing the temporal relationship of these conformers within a conformational trajectory is not trivial. Here, we use thermal titration methods and cryo-EM in an attempt to obtain temporal resolution of the conformational trajectory of the vanilloid receptor TRPV1 with resiniferatoxin (RTx) bound. Based on our cryo-EM ensemble analysis, RTx binding to TRPV1 appears to induce intracellular gate opening first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state. This apparent conformational wave likely arises from the concerted, stepwise, additive structural changes of TRPV1 over many subdomains. Greater understanding of the RTx-mediated long-range allostery of TRPV1 could help further the therapeutic potential of RTx, which is a promising drug candidate for pain relief associated with advanced cancer or knee arthritis. Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis.,Kwon DH, Zhang F, Fedor JG, Suo Y, Lee SY Nat Commun. 2022 May 24;13(1):2874. doi: 10.1038/s41467-022-30602-2. PMID:35610228[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 6 reviews cite this structure No citations found See AlsoReferences
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