6DMU

PI(4,5)P2 bound full-length rbTRPV5

Summary for 6DMU

• Entry DOI: 10.2210/pdb6dmu/pdb
• EMDB information: 7966
• Descriptor: Transient receptor potential cation channel subfamily V member 5, [(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 (2 entities in total)
• Functional Keywords: pi(4, 5)p2, trpv5, full-length, ion channel, transport protein
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 4
• Total formula weight: 334584.89

Authors

Hughes, T.E.T.,Pumroy, R.A.,Moiseenkova-Bell, V.Y. (deposition date: 2018-06-05, release date: 2018-10-24, Last modification date: 2024-03-13)

Primary citation

Hughes, T.E.T.,Pumroy, R.A.,Yazici, A.T.,Kasimova, M.A.,Fluck, E.C.,Huynh, K.W.,Samanta, A.,Molugu, S.K.,Zhou, Z.H.,Carnevale, V.,Rohacs, T.,Moiseenkova-Bell, V.Y.
Structural insights on TRPV5 gating by endogenous modulators.
Nat Commun, 9:4198-4198, 2018

PubMed Abstract: 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.

PubMed: 30305626
DOI: 10.1038/s41467-018-06753-6

Experimental method

ELECTRON MICROSCOPY (4 Å)