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Structural insights on TRPV5 gating by endogenous modulators.

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
Nat Commun 9 4198 (2018)
Related entries: 6dmr, 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 - 6dmu mentioned but not cited (7)

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Articles - 6dmu mentioned but not cited (9)

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  25. 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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  37. 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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  41. Modulation of Calcium Homeostasis May Be Associated with Susceptibility to Renal Cell Carcinoma in Diabetic Nephropathy Rats. Luo Y, Lu Z, Waaga-Gasser AM, Yang H, Liu J, Wu J, Lu J, Liu X, Zhang L. Cancer Manag Res 12 9679-9689 (2020)
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  43. 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)
  44. Molecular insights into the structural and dynamical changes of calcium channel TRPV6 induced by its interaction with phosphatidylinositol 4,5-bisphosphate. Wang L, Cai R, Chen XZ, Peng JB. J Biomol Struct Dyn 41 6559-6568 (2023)
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