Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.
Journal, issue, pages	Nat Commun, Vol. 14, Issue 1, Page 3732, Year 2023
Publish date	Jun 23, 2023
Authors	Do Hoon Kwon / Feng Zhang / Brett A McCray / Shasha Feng / Meha Kumar / Jeremy M Sullivan / Wonpil Im / Charlotte J Sumner / Seok-Yong Lee /
PubMed Abstract	Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, ...Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.
External links	Nat Commun / PubMed:37353484 / PubMed Central
Methods	EM (single particle)
Resolution	3.2 - 3.75 Å
Structure data	28975 8fc7 EMDB-28975, PDB-8fc7: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK2798745 Method: EM (single particle) / Resolution: 3.3 Å 28976 8fc8 8fcb EMDB-28976, PDB-8fc8: Cryo-EM structure of the human TRPV4 in complex with GSK1016790A PDB-8fcb: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK1016790A Method: EM (single particle) / Resolution: 3.47 Å 28977 8fc9 EMDB-28977, PDB-8fc9: Cryo-EM structure of the human TRPV4 - RhoA, apo condition Method: EM (single particle) / Resolution: 3.75 Å 28978 8fca EMDB-28978, PDB-8fca: Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alpha-Phorbol 12,13-didecanoate Method: EM (single particle) / Resolution: 3.41 Å EMDB-29030: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK2798745, TRPV4 focused refinement map Method: EM (single particle) / Resolution: 3.3 Å EMDB-29031: Cryo-EM structure of the human TRPV4 - RhoA in complex with GSK2798745, RhoA focused refinement map Method: EM (single particle) / Resolution: 3.2 Å EMDB-29331: Cryo-EM structure of the human TRPV4 in complex with GSK1016790A, TRPV4 focused refinement map Method: EM (single particle) / Resolution: 3.5 Å EMDB-29332: Cryo-EM structure of the human TRPV4 in complex with GSK1016790A, RhoA focused refinement map Method: EM (single particle) / Resolution: 3.4 Å
Chemicals	ChemComp-XPW: 1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl}methyl)-1H-benzimidazole-6-carbonitrile ChemComp-MG: Unknown entry ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying moleculeYM / Guanosine diphosphate ChemComp-XQ3: N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazin-1-yl}-4-methyl-1-oxopentan-2-yl]-1-benzothiophene-2-carboxamide ChemComp-Y01: CHOLESTEROL HEMISUCCINATE 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-GSP*: 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN/Hydrolase / TRPV4 / RhoA / GSK2798745 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Hydrolase complex / GSK1016790A / 4alpha-Phorbol 12 / 13-didecanoate / 4a-PDD