タイトル Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. ジャーナル・号・ページ Cell , Vol. 184, Issue 20, Page 5138-5150.e12, Year 2021掲載日 2021年9月30日 著者Kaihua Zhang / David Julius / Yifan Cheng / PubMed 要旨 Many transient receptor potential (TRP) channels respond to diverse stimuli and conditionally conduct small and large cations. Such functional plasticity is presumably enabled by a uniquely dynamic ... Many transient receptor potential (TRP) channels respond to diverse stimuli and conditionally conduct small and large cations. Such functional plasticity is presumably enabled by a uniquely dynamic ion selectivity filter that is regulated by physiological agents. What is currently missing is a "photo series" of intermediate structural states that directly address this hypothesis and reveal specific mechanisms behind such dynamic channel regulation. Here, we exploit cryoelectron microscopy (cryo-EM) to visualize conformational transitions of the capsaicin receptor, TRPV1, as a model to understand how dynamic transitions of the selectivity filter in response to algogenic agents, including protons, vanilloid agonists, and peptide toxins, permit permeation by small and large organic cations. These structures also reveal mechanisms governing ligand binding substates, as well as allosteric coupling between key sites that are proximal to the selectivity filter and cytoplasmic gate. These insights suggest a general framework for understanding how TRP channels function as polymodal signal integrators. リンク Cell / PubMed:34496225 / PubMed Central手法 EM (単粒子) 解像度 2.6 - 3.89 Å 構造データ EMDB-23128 , PDB-7l2h : Cryo-EM structure of unliganded full-length TRPV1 at neutral pH 手法 : EM (単粒子) / 解像度 : 2.63 Å
EMDB-23129 , PDB-7l2i : Cryo-EM structure of full-length TRPV1 at pH6a state手法 : EM (単粒子) / 解像度 : 3.7 Å
EMDB-23130 , PDB-7l2j : Cryo-EM structure of full-length TRPV1 at pH6c state手法 : EM (単粒子) / 解像度 : 3.66 Å
EMDB-23131 , PDB-7l2k : Cryo-EM structure of full-length TRPV1 at pH6b state手法 : EM (単粒子) / 解像度 : 3.89 Å
EMDB-23132 , PDB-7l2l : Cryo-EM structure of RTX-bound full-length TRPV1 in O1 state手法 : EM (単粒子) / 解像度 : 3.42 Å
EMDB-23133 , PDB-7l2m : Cryo-EM structure of DkTx/RTX-bound full-length TRPV1手法 : EM (単粒子) / 解像度 : 3.84 Å
EMDB-23134 , PDB-7l2n : Cryo-EM structure of RTX-bound full-length TRPV1 in C1 state手法 : EM (単粒子) / 解像度 : 3.09 Å
EMDB-23135 , PDB-7l2o : Cryo-EM structure of RTX-bound full-length TRPV1 at pH 5.5 手法 : EM (単粒子) / 解像度 : 3.64 Å
EMDB-23136 , PDB-7l2p : cryo-EM structure of unliganded minimal TRPV1手法 : EM (単粒子) / 解像度 : 2.6 Å
EMDB-23138 , PDB-7l2r : Cryo-EM structure of DkTx-bound minimal TRPV1 at the pre-open state手法 : EM (単粒子) / 解像度 : 3.3 Å
EMDB-23139 , PDB-7l2s : cryo-EM structure of DkTx-bound minimal TRPV1 at the pre-bound state手法 : EM (単粒子) / 解像度 : 2.71 Å
EMDB-23140 , PDB-7l2t : cryo-EM structure of DkTx-bound minimal TRPV1 in partial open state手法 : EM (単粒子) / 解像度 : 3.08 Å
EMDB-23141 , PDB-7l2u : cryo-EM structure of DkTx-bound minimal TRPV1 in open state手法 : EM (単粒子) / 解像度 : 3.47 Å
EMDB-23142 , PDB-7l2v : cryo-EM structure of RTX-bound minimal TRPV1 with NMDG at state b 手法 : EM (単粒子) / 解像度 : 3.64 Å
EMDB-23143 , PDB-7l2w : cryo-EM structure of RTX-bound minimal TRPV1 with NMDG at state a 手法 : EM (単粒子) / 解像度 : 3.16 Å
EMDB-23144 , PDB-7l2x : cryo-EM structure of RTX-bound minimal TRPV1 with NMDG at state c 手法 : EM (単粒子) / 解像度 : 3.26 Å
EMDB-23161 : ムービー 構造ビューア Cryo-EM structure of DkTx-bound minimal TRPV1 at the singly-bound state手法 : EM (単粒子) / 解像度 : 3.03 Å
EMDB-24083 , PDB-7mz5 : Cryo-EM structure of RTX-bound full-length TRPV1 in C2 state手法 : EM (単粒子) / 解像度 : 2.76 Å
EMDB-24084 , PDB-7mz6 : Cryo-EM structure of minimal TRPV1 with 1 perturbed PI 手法 : EM (単粒子) / 解像度 : 2.91 Å
EMDB-24085 , PDB-7mz7 : Cryo-EM structure of minimal TRPV1 with 4 partially bound RTX手法 : EM (単粒子) / 解像度 : 3.35 Å
EMDB-24086 , PDB-7mz9 : Cryo-EM structure of minimal TRPV1 with 1 partially bound RTX 手法 : EM (単粒子) / 解像度 : 3.18 Å
EMDB-24087 , PDB-7mza : Cryo-EM structure of minimal TRPV1 with 2 bound RTX in adjacent pockets手法 : EM (単粒子) / 解像度 : 3.46 Å
EMDB-24088 , PDB-7mzb : Cryo-EM structure of minimal TRPV1 with 3 bound RTX and 1 perturbed PI手法 : EM (単粒子) / 解像度 : 3.72 Å
EMDB-24089 , PDB-7mzc : Cryo-EM structure of minimal TRPV1 with RTX bound in C1 state手法 : EM (単粒子) / 解像度 : 3.03 Å
EMDB-24090 , PDB-7mzd : Cryo-EM structure of minimal TRPV1 with RTX bound in C2 state手法 : EM (単粒子) / 解像度 : 2.9 Å
EMDB-24091 , PDB-7mze : Cryo-EM structure of minimal TRPV1 with 2 bound RTX in opposite pockets手法 : EM (単粒子) / 解像度 : 3.42 Å
化合物 ChemComp-XJ7 : 構造ビューア (2S)-1-(butanoyloxy)-3-{[(R)-hydroxy{[(1r,2R,3S,4S,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propan-2-yl tridecanoate
ChemComp-XJD : 構造ビューア (10R,13S)-16-amino-13-hydroxy-7,13-dioxo-8,12,14-trioxa-13lambda~5~-phosphahexadecan-10-yl tridecanoate
ChemComp-XJA : 構造ビューア (2S)-1-(butanoyloxy)-3-{[(R)-hydroxy{[(1S,2R,3R,4R,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propan-2-yl tridecanoate
ChemComp-6IY : 構造ビューア (10R,13S)-16-amino-13-hydroxy-7,13-dioxo-8,12,14-trioxa-13lambda~5~-phosphahexadecan-10-yl hexadecanoate
ChemComp-65I : 構造ビューア (9R,12R)-15-amino-12-hydroxy-6,12-dioxo-7,11,13-trioxa-12lambda~5~-phosphapentadecan-9-yl undecanoate
ChemComp-XKP : 構造ビューア (11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate
由来 rattus norvegicus (ドブネズミ)Cyriopagopus schmidtiCyriopagopus schmidti (クモ)cyriopagopus schmidti (クモ) キーワード TRANSPORT PROTEIN / TRP channel / cryo-EM / nanodisc / full length / proton / vanilloid agonist / toxin / large cation / stoichiometry