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Structural insights on TRPV5 gating by endogenous modulators.

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Hughes TET, Pumroy RA, Yazici AT, Kasimova MA, Fluck EC, Huynh KW, Samanta A, Molugu SK, Zhou ZH, Carnevale V, Rohacs T, Moiseenkova-Bell VY
OpenAccess logo Nat Commun 9 4198 (2018)
Related entries: 6dmu, 6dmw

Cited: 83 times
EuropePMC logo PMID: 30305626

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)P2) 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)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5. These interactions with PI(4,5)P2 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.

Reviews - 6dmr mentioned but not cited (1)

  1. Structural insights into the gating mechanisms of TRPV channels. Pumroy RA, Fluck EC, Ahmed T, Moiseenkova-Bell VY. Cell Calcium 87 102168 (2020)

Articles - 6dmr mentioned but not cited (5)

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  4. Interhelical H-Bonds Modulate the Activity of a Polytopic Transmembrane Kinase. Almada JC, Bortolotti A, Ruysschaert JM, de Mendoza D, Inda ME, Cybulski LE. Biomolecules 11 938 (2021)
  5. Intracellular Helix-Loop-Helix Domain Modulates Inactivation Kinetics of Mammalian TRPV5 and TRPV6 Channels. Flores-Aldama L, Bustos D, Cabezas-Bratesco D, Gonzalez W, Brauchi SE. Int J Mol Sci 24 4470 (2023)


Reviews citing this publication (23)

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Articles citing this publication (54)

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  28. Theoretical Study of the Structural Stability, Chemical Reactivity, and Protein Interaction for NMP Compounds as Modulators of the Endocannabinoid System. Rangel-Galván M, Castro ME, Perez-Aguilar JM, Caballero NA, Rangel-Huerta A, Melendez FJ. Molecules 27 414 (2022)
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  42. Conceptual DFT, QTAIM, and Molecular Docking Approaches to Characterize the T-Type Calcium Channel Blocker Anandamide. Rangel-Galván M, Castro ME, Perez-Aguilar JM, Caballero NA, Melendez FJ. Front Chem 10 920661 (2022)
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  48. Molecular details of ruthenium red pore block in TRPV channels. Pumroy RA, De Jesús-Pérez JJ, Protopopova AD, Rocereta JA, Fluck EC, Fricke T, Lee BH, Rohacs T, Leffler A, Moiseenkova-Bell V. EMBO Rep 25 506-523 (2024)
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  52. Functional characterization of the transient receptor potential melastatin 2 (TRPM2) cation channel from Nematostella vectensis reconstituted into lipid bilayer. Szollosi A, Almássy J. Sci Rep 13 11471 (2023)
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