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Nat Struct Mol Biol
2018 Jan 01;251:53-60. doi: 10.1038/s41594-017-0009-1.
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Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.
Hughes TET
,
Lodowski DT
,
Huynh KW
,
Yazici A
,
Del Rosario J
,
Kapoor A
,
Basak S
,
Samanta A
,
Han X
,
Chakrapani S
,
Zhou ZH
,
Filizola M
,
Rohacs T
,
Han S
,
Moiseenkova-Bell VY
.
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The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca2+, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca2+ reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels. The econazole-bound TRPV5 structure adopts a closed conformation with a distinct lower gate that occludes Ca2+ permeation through the channel. Structural comparisons between TRPV5 and other TRPV channels, complemented with molecular dynamics (MD) simulations of the econazole-bound TRPV5 structure, allowed us to gain mechanistic insight into TRPV5 channel inhibition by small molecules.
Adams,
PHENIX: building new software for automated crystallographic structure determination.
2002, Pubmed
Adams,
PHENIX: building new software for automated crystallographic structure determination.
2002,
Pubmed
Best,
Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles.
2012,
Pubmed
Bussi,
Canonical sampling through velocity rescaling.
2007,
Pubmed
Cao,
TRPV1 structures in distinct conformations reveal activation mechanisms.
2013,
Pubmed
Catterall,
The chemical basis for electrical signaling.
2017,
Pubmed
Catterall,
Ion channel voltage sensors: structure, function, and pathophysiology.
2010,
Pubmed
Cvetkov,
Molecular architecture and subunit organization of TRPA1 ion channel revealed by electron microscopy.
2011,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Eswar,
Comparative protein structure modeling using MODELLER.
2007,
Pubmed
Fecher-Trost,
TRPV6: From identification to function.
2017,
Pubmed
Feng,
Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations.
2015,
Pubmed
Gao,
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.
2016,
Pubmed
Grieben,
Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2).
2017,
Pubmed
Hoenderop,
Function and expression of the epithelial Ca(2+) channel family: comparison of mammalian ECaC1 and 2.
2001,
Pubmed
Hoover,
Canonical dynamics: Equilibrium phase-space distributions.
1985,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Huynh,
Structure of the full-length TRPV2 channel by cryo-EM.
2016,
Pubmed
Huynh,
Structural insight into the assembly of TRPV channels.
2014,
Pubmed
Jo,
CHARMM-GUI: a web-based graphical user interface for CHARMM.
2008,
Pubmed
Klauda,
Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types.
2010,
Pubmed
Kucukelbir,
Quantifying the local resolution of cryo-EM density maps.
2014,
Pubmed
Landowski,
Chemical inhibitors of the calcium entry channel TRPV6.
2011,
Pubmed
Lee,
CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field.
2016,
Pubmed
Li,
Structural basis of dual Ca2+/pH regulation of the endolysosomal TRPML1 channel.
2017,
Pubmed
Liao,
Structure of the TRPV1 ion channel determined by electron cryo-microscopy.
2013,
Pubmed
MacKerell,
All-atom empirical potential for molecular modeling and dynamics studies of proteins.
1998,
Pubmed
Moiseenkova-Bell,
Structure of TRPV1 channel revealed by electron cryomicroscopy.
2008,
Pubmed
Na,
TRPV5: a Ca(2+) channel for the fine-tuning of Ca(2+) reabsorption.
2014,
Pubmed
Nie,
Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients.
2016,
Pubmed
Nilius,
Pharmacological modulation of monovalent cation currents through the epithelial Ca2+ channel ECaC1.
2001,
Pubmed
Paulsen,
Structure of the TRPA1 ion channel suggests regulatory mechanisms.
2015,
Pubmed
Phelps,
Structural analyses of the ankyrin repeat domain of TRPV6 and related TRPV ion channels.
2008,
Pubmed
Potter,
Leginon: a system for fully automated acquisition of 1000 electron micrographs a day.
1999,
Pubmed
Renkema,
Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice.
2005,
Pubmed
Saotome,
Crystal structure of the epithelial calcium channel TRPV6.
2016,
Pubmed
Scales,
Prevalence of kidney stones in the United States.
2012,
Pubmed
Scherer,
PyEMMA 2: A Software Package for Estimation, Validation, and Analysis of Markov Models.
2015,
Pubmed
Scheres,
RELION: implementation of a Bayesian approach to cryo-EM structure determination.
2012,
Pubmed
Scheres,
Processing of Structurally Heterogeneous Cryo-EM Data in RELION.
2016,
Pubmed
Shen,
Statistical potential for assessment and prediction of protein structures.
2006,
Pubmed
Shen,
The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs.
2016,
Pubmed
Singh,
Swapping of transmembrane domains in the epithelial calcium channel TRPV6.
2017,
Pubmed
Tang,
Structural basis for Ca2+ selectivity of a voltage-gated calcium channel.
2014,
Pubmed
Van Der Spoel,
GROMACS: fast, flexible, and free.
2005,
Pubmed
van der Wijst,
A Gate Hinge Controls the Epithelial Calcium Channel TRPV5.
2017,
Pubmed
van Goor,
TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6.
2017,
Pubmed
Vanommeslaeghe,
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields.
2010,
Pubmed
Velisetty,
A molecular determinant of phosphoinositide affinity in mammalian TRPV channels.
2016,
Pubmed
Venkatachalam,
TRP channels.
2007,
Pubmed
Wang,
I-TASSER-MR: automated molecular replacement for distant-homology proteins using iterative fragment assembly and progressive sequence truncation.
2017,
Pubmed
Wilkes,
Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2.
2017,
Pubmed
Wu,
Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution.
2016,
Pubmed
Yang,
Rational design and validation of a vanilloid-sensitive TRPV2 ion channel.
2016,
Pubmed
Zhang,
Engineering vanilloid-sensitivity into the rat TRPV2 channel.
2016,
Pubmed
Zhang,
Gctf: Real-time CTF determination and correction.
2016,
Pubmed
Zheng,
MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy.
2017,
Pubmed
Zubcevic,
Cryo-electron microscopy structure of the TRPV2 ion channel.
2016,
Pubmed
