Loading
PDBj
MenuPDBj@FacebookPDBj@TwitterPDBj@YouTubewwPDB FoundationwwPDB
RCSB PDBPDBeBMRBAdv. SearchSearch help

8T1E

Closed-state cryo-EM structure of full-length human TRPV4 in the presence of 4a-PDD

Summary for 8T1E
Entry DOI10.2210/pdb8t1e/pdb
Related8T1B 8T1C 8T1D
EMDB information40958 40959 40960 40961
DescriptorTransient receptor potential cation channel subfamily V member 4,Enhanced green fluorescent protein, [(2~{R})-2-[(~{Z})-hexadec-9-enoyl]oxy-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propyl] (~{Z})-docos-13-enoate, (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, ... (5 entities in total)
Functional Keywordstransient receptor potential v family member 4, trp, channel, trpv4, trp channels, membrane protein, agonist, 4a-pdd, 4alpha-phorbol 12, 13-didecanoate, closed state
Biological sourceHomo sapiens (human)
More
Total number of polymer chains4
Total formula weight546348.84
Authors
Talyzina, I.A.,Nadezhdin, K.D.,Neuberger, A.,Sobolevsky, A.I. (deposition date: 2023-06-02, release date: 2023-07-05, Last modification date: 2024-10-16)
Primary citationNadezhdin, K.D.,Talyzina, I.A.,Parthasarathy, A.,Neuberger, A.,Zhang, D.X.,Sobolevsky, A.I.
Structure of human TRPV4 in complex with GTPase RhoA.
Nat Commun, 14:3733-3733, 2023
Cited by
PubMed Abstract: 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.
PubMed: 37353478
DOI: 10.1038/s41467-023-39346-z
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (2.77 Å)
Structure validation

227344

PDB entries from 2024-11-13

PDB statisticsPDBj update infoContact PDBjnumon