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Structure paper

TitleStructure of human TRPV4 in complex with GTPase RhoA.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3733, Year 2023
Publish dateJun 23, 2023
AuthorsKirill D Nadezhdin / Irina A Talyzina / Aravind Parthasarathy / Arthur Neuberger / David X Zhang / Alexander I Sobolevsky /
PubMed AbstractTransient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in ...Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.
External linksNat Commun / PubMed:37353478 / PubMed Central
MethodsEM (single particle)
Resolution2.77 - 3.49 Å
Structure data

EMDB-40958, PDB-8t1b:
Cryo-EM structure of full-length human TRPV4 in apo state
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-40959, PDB-8t1c:
Cryo-EM structure of human TRPV4 ankyrin repeat domain in complex with GTPase RhoA
Method: EM (single particle) / Resolution: 3.49 Å

EMDB-40960, PDB-8t1d:
Open-state cryo-EM structure of full-length human TRPV4 in complex with agonist 4a-PDD
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-40961, PDB-8t1e:
Closed-state cryo-EM structure of full-length human TRPV4 in the presence of 4a-PDD
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-40962, PDB-8t1f:
Cryo-EM structure of full-length human TRPV4 in complex with antagonist HC-067047
Method: EM (single particle) / Resolution: 3.49 Å

Chemicals

ChemComp-9ZR:
[(2~{R})-2-[(~{Z})-hexadec-9-enoyl]oxy-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propyl] (~{Z})-docos-13-enoate

ChemComp-YJ0:
(2R)-2-{[(4-O-hexopyranosyl-beta-D-glucopyranosyl)oxy]methyl}-4-{[(25R)-5beta,14beta,17beta-spirostan-3beta-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-XS9:
(1aR,1bS,4aS,7aS,7bS,8R,9R,9aS)-9a-(decanoyloxy)-4a,7b-dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl decanoate

ChemComp-X7N:
2-methyl-1-[3-(morpholin-4-yl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

Source
  • homo sapiens (human)
  • human betaherpesvirus 5
  • human cytomegalovirus
KeywordsMEMBRANE PROTEIN / transient receptor potential V family member 4 / TRP / channel / TRPV4 / TRP channels / GTPase / transforming protein RhoA / RhoA / ankyrin repeat domain / GDP / guanosine diphosphate / agonist / 4a-PDD / open state / 4alpha-Phorbol 12 / 13-didecanoate / closed state / antagonist / inhibited state / HC-067047

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