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TitleStructural insights on TRPV5 gating by endogenous modulators.
Journal, issue, pagesNat Commun, Vol. 9, Issue 1, Page 4198, Year 2018
Publish dateOct 10, 2018
AuthorsTaylor E T Hughes / Ruth A Pumroy / Aysenur Torun Yazici / Marina A Kasimova / Edwin C Fluck / Kevin W Huynh / Amrita Samanta / Sudheer K Molugu / Z Hong Zhou / Vincenzo Carnevale / Tibor Rohacs / Vera Y Moiseenkova-Bell /
PubMed AbstractTRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5- ...TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P and CaM. The PI(4,5)P structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P induce conformational rearrangements in the lower gate, opening the channel. The CaM structure reveals two TRPV5 C-terminal peptides anchoring a single CaM molecule and that calcium inhibition is mediated through a cation-π interaction between Lys116 on the C-lobe of calcium-activated CaM and Trp583 at the intracellular gate of TRPV5. Overall, this investigation provides insight into the endogenous modulation of TRPV5, which has the potential to guide drug discovery.
External linksNat Commun / PubMed:30305626 / PubMed Central
MethodsEM (single particle)
Resolution3.9 - 4.4 Å
Structure data

EMDB-7965, PDB-6dmr:
Lipid-bound full-length rbTRPV5
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-7966, PDB-6dmu:
PI(4,5)P2 bound full-length rbTRPV5
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-7967, PDB-6dmw:
Calmodulin-bound full-length rbTRPV5
Method: EM (single particle) / Resolution: 4.4 Å

Chemicals

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-CA:
Unknown entry

Source
  • oryctolagus cuniculus (rabbit)
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / TRPV5 / calcium channel / lipid-bound / full-length / PI(4 / 5)P2 / ion channel / calmodulin

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