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- EMDB-7058: Structure of TRPV5 in complex with econazole -

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Basic information

Entry
Database: EMDB / ID: EMD-7058
TitleStructure of TRPV5 in complex with econazole
Map dataTRPV5 in complex with econazole
Sample
  • Complex: Full-length TRPV5 in complex with econazole
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 5
  • Ligand: 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
  • Ligand: CALCIUM IONCalcium
KeywordsTRPV5 / Econazole / Transient Receptor Potential Channel / Cryo-EM / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of urine volume / calcium ion import across plasma membrane / calcium ion homeostasis / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / protein homotetramerization / calmodulin binding / apical plasma membrane / identical protein binding ...regulation of urine volume / calcium ion import across plasma membrane / calcium ion homeostasis / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / protein homotetramerization / calmodulin binding / apical plasma membrane / identical protein binding / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 5 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential cation channel subfamily V member 5 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily V member 5
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.8 Å
AuthorsHughes TET / Lodowski DT
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIGMS 1R01GM103899-01A1 United States
CitationJournal: Nat Struct Mol Biol / Year: 2018
Title: Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.
Authors: Taylor E T Hughes / David T Lodowski / Kevin W Huynh / Aysenur Yazici / John Del Rosario / Abhijeet Kapoor / Sandip Basak / Amrita Samanta / Xu Han / Sudha Chakrapani / Z Hong Zhou / Marta ...Authors: Taylor E T Hughes / David T Lodowski / Kevin W Huynh / Aysenur Yazici / John Del Rosario / Abhijeet Kapoor / Sandip Basak / Amrita Samanta / Xu Han / Sudha Chakrapani / Z Hong Zhou / Marta Filizola / Tibor Rohacs / Seungil Han / Vera Y Moiseenkova-Bell /
Abstract: The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca, that is present primarily at the ...The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca 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 Ca 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.
History
DepositionSep 29, 2017-
Header (metadata) releaseNov 8, 2017-
Map releaseDec 27, 2017-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6b5v
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7058.png

Downloads & links

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Map

FileDownload / File: emd_7058.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTRPV5 in complex with econazole
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.04 / Movie #1: 0.04
Minimum - Maximum-0.07627523 - 0.13983618
Average (Standard dev.)0.0016641174 (±0.008344924)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-192-1920
Dimensions192192192
Spacing192192192
CellA=B=C: 211.20001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z211.200211.200211.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS-192-1920
NC/NR/NS192192192
D min/max/mean-0.0760.1400.002

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Supplemental data

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Sample components

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Entire : Full-length TRPV5 in complex with econazole

EntireName: Full-length TRPV5 in complex with econazole
Components
  • Complex: Full-length TRPV5 in complex with econazole
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 5
  • Ligand: 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
  • Ligand: CALCIUM IONCalcium

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Supramolecule #1: Full-length TRPV5 in complex with econazole

SupramoleculeName: Full-length TRPV5 in complex with econazole / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Oryctolagus cuniculus (rabbit)

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 5

MacromoleculeName: Transient receptor potential cation channel subfamily V member 5
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 82.899656 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString: MGACPPKAKG PWAQLQKLLI SWPVGEQDWE QYRDRVNMLQ QERIRDSPLL QAAKENDLRL LKILLLNQSC DFQQRGAVGE TALHVAALY DNLEAATLLM EAAPELAKEP ALCEPFVGQT ALHIAVMNQN LNLVRALLAR GASVSARATG AAFRRSPHNL I YYGEHPLS ...String:
MGACPPKAKG PWAQLQKLLI SWPVGEQDWE QYRDRVNMLQ QERIRDSPLL QAAKENDLRL LKILLLNQSC DFQQRGAVGE TALHVAALY DNLEAATLLM EAAPELAKEP ALCEPFVGQT ALHIAVMNQN LNLVRALLAR GASVSARATG AAFRRSPHNL I YYGEHPLS FAACVGSEEI VRLLIEHGAD IRAQDSLGNT VLHILILQPN KTFACQMYNL LLSYDEHSDH LQSLELVPNH QG LTPFKLA GVEGNTVMFQ HLMQKRKHVQ WTCGPLTSTL YDLTEIDSWG EELSFLELVV SSKKREARQI LEQTPVKELV SFK WKKYGR PYFCVLASLY ILYMICFTTC CIYRPLKLRD DNRTDPRDIT ILQQKLLQEA YVTHQDNIRL VGELVTVTGA VIIL LLEIP DIFRVGASRY FGQTILGGPF HVIIITYASL VLLTMVMRLT NMNGEVVPLS FALVLGWCSV MYFARGFQML GPFTI MIQK MIFGDLMRFC WLMAVVILGF ASAFHITFQT EDPNNLGEFS DYPTALFSTF ELFLTIIDGP ANYSVDLPFM YCITYA AFA IIATLLMLNL FIAMMGDTHW RVAQERDELW RAQVVATTVM LERKMPRFLW PRSGICGYEY GLGDRWFLRV ENHHDQN PL RVLRYVEAFK CSDKEDGQEQ LSEKRPSTVE SGMLSRASVA FQTPSLSRTT SQSSNSHRGW EILRRNTLGH LNLGLDLG E GDGEEVYHF

UniProtKB: Transient receptor potential cation channel subfamily V member 5

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Macromolecule #2: 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-i...

MacromoleculeName: 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
type: ligand / ID: 2 / Number of copies: 4 / Formula: ECL
Molecular weightTheoretical: 381.684 Da
Chemical component information

ChemComp-ECL:
1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chlorideSodium Chloride
20.0 mMC8H18N2O4SHEPES
0.064 mMC43H80O22DMNG
2.0 mMC9H15O6PTCEP
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal magnification: 45455
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Number real images: 3313 / Average exposure time: 0.2 sec. / Average electron dose: 2.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 925927
Startup modelType of model: EMDB MAP
EMDB ID:

6580

Initial angle assignmentType: COMMON LINE / Software - Name: RELION (ver. 2.0)
Final angle assignmentType: COMMON LINE / Software - Name: RELION (ver. 2.0)
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 50566
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER / Target criteria: correlation coefficient
Output model

PDB-6b5v:
Structure of TRPV5 in complex with econazole

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