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Structure paper

TitleStructural snapshots of TRPV1 reveal mechanism of polymodal functionality.
Journal, issue, pagesCell, Vol. 184, Issue 20, Page 5138-5150.e12, Year 2021
Publish dateSep 30, 2021
AuthorsKaihua Zhang / David Julius / Yifan Cheng /
PubMed AbstractMany 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.
External linksCell / PubMed:34496225 / PubMed Central
MethodsEM (single particle)
Resolution2.6 - 3.89 Å
Structure data

EMDB-23128, PDB-7l2h:
Cryo-EM structure of unliganded full-length TRPV1 at neutral pH
Method: EM (single particle) / Resolution: 2.63 Å

EMDB-23129, PDB-7l2i:
Cryo-EM structure of full-length TRPV1 at pH6a state
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-23130, PDB-7l2j:
Cryo-EM structure of full-length TRPV1 at pH6c state
Method: EM (single particle) / Resolution: 3.66 Å

EMDB-23131, PDB-7l2k:
Cryo-EM structure of full-length TRPV1 at pH6b state
Method: EM (single particle) / Resolution: 3.89 Å

EMDB-23132, PDB-7l2l:
Cryo-EM structure of RTX-bound full-length TRPV1 in O1 state
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-23133, PDB-7l2m:
Cryo-EM structure of DkTx/RTX-bound full-length TRPV1
Method: EM (single particle) / Resolution: 3.84 Å

EMDB-23134, PDB-7l2n:
Cryo-EM structure of RTX-bound full-length TRPV1 in C1 state
Method: EM (single particle) / Resolution: 3.09 Å

EMDB-23135, PDB-7l2o:
Cryo-EM structure of RTX-bound full-length TRPV1 at pH 5.5
Method: EM (single particle) / Resolution: 3.64 Å

EMDB-23136, PDB-7l2p:
cryo-EM structure of unliganded minimal TRPV1
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-23138, PDB-7l2r:
Cryo-EM structure of DkTx-bound minimal TRPV1 at the pre-open state
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-23139, PDB-7l2s:
cryo-EM structure of DkTx-bound minimal TRPV1 at the pre-bound state
Method: EM (single particle) / Resolution: 2.71 Å

EMDB-23140, PDB-7l2t:
cryo-EM structure of DkTx-bound minimal TRPV1 in partial open state
Method: EM (single particle) / Resolution: 3.08 Å

EMDB-23141, PDB-7l2u:
cryo-EM structure of DkTx-bound minimal TRPV1 in open state
Method: EM (single particle) / Resolution: 3.47 Å

EMDB-23142, PDB-7l2v:
cryo-EM structure of RTX-bound minimal TRPV1 with NMDG at state b
Method: EM (single particle) / Resolution: 3.64 Å

EMDB-23143, PDB-7l2w:
cryo-EM structure of RTX-bound minimal TRPV1 with NMDG at state a
Method: EM (single particle) / Resolution: 3.16 Å

EMDB-23144, PDB-7l2x:
cryo-EM structure of RTX-bound minimal TRPV1 with NMDG at state c
Method: EM (single particle) / Resolution: 3.26 Å

EMDB-23161:
Cryo-EM structure of DkTx-bound minimal TRPV1 at the singly-bound state
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-24083, PDB-7mz5:
Cryo-EM structure of RTX-bound full-length TRPV1 in C2 state
Method: EM (single particle) / Resolution: 2.76 Å

EMDB-24084, PDB-7mz6:
Cryo-EM structure of minimal TRPV1 with 1 perturbed PI
Method: EM (single particle) / Resolution: 2.91 Å

EMDB-24085, PDB-7mz7:
Cryo-EM structure of minimal TRPV1 with 4 partially bound RTX
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-24086, PDB-7mz9:
Cryo-EM structure of minimal TRPV1 with 1 partially bound RTX
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-24087, PDB-7mza:
Cryo-EM structure of minimal TRPV1 with 2 bound RTX in adjacent pockets
Method: EM (single particle) / Resolution: 3.46 Å

EMDB-24088, PDB-7mzb:
Cryo-EM structure of minimal TRPV1 with 3 bound RTX and 1 perturbed PI
Method: EM (single particle) / Resolution: 3.72 Å

EMDB-24089, PDB-7mzc:
Cryo-EM structure of minimal TRPV1 with RTX bound in C1 state
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-24090, PDB-7mzd:
Cryo-EM structure of minimal TRPV1 with RTX bound in C2 state
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-24091, PDB-7mze:
Cryo-EM structure of minimal TRPV1 with 2 bound RTX in opposite pockets
Method: EM (single particle) / Resolution: 3.42 Å

Chemicals

ChemComp-XJ7:
(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:
(10R,13S)-16-amino-13-hydroxy-7,13-dioxo-8,12,14-trioxa-13lambda~5~-phosphahexadecan-10-yl tridecanoate

ChemComp-NA:
Unknown entry

ChemComp-XJA:
(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-6EU:
resiniferatoxin / toxin*YM

ChemComp-6IY:
(10R,13S)-16-amino-13-hydroxy-7,13-dioxo-8,12,14-trioxa-13lambda~5~-phosphahexadecan-10-yl hexadecanoate

ChemComp-65I:
(9R,12R)-15-amino-12-hydroxy-6,12-dioxo-7,11,13-trioxa-12lambda~5~-phosphapentadecan-9-yl undecanoate

ChemComp-HOH:
WATER

ChemComp-XKP:
(11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate

ChemComp-XPS:
6-deoxy-6-(methylamino)-D-galactitol

ChemComp-XPJ:
1-deoxy-1-(methylamino)-D-allitol

Source
  • rattus norvegicus (Norway rat)
  • Cyriopagopus schmidtiCyriopagopus schmidti (Chinese earth tiger)
  • cyriopagopus schmidti (Chinese earth tiger)
KeywordsTRANSPORT PROTEIN / TRP channel / cryo-EM / nanodisc / full length / proton / vanilloid agonist / toxin / large cation / stoichiometry

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