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- PDB-6d7x: Crystal Structure of Rat TRPV6*-Y466A- in complex with brominated... -

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Entry
Database: PDB / ID: 6d7x
TitleCrystal Structure of Rat TRPV6*-Y466A- in complex with brominated 2-Aminoethoxydiphenyl borate (2-APB-Br)
ComponentsTransient receptor potential cation channel subfamily V member 6
Keywordsmembrane protein/inhibitor / Ion channels / transporter / calcium channel / epithelial calcium channel / MEMBRANE PROTEIN / membrane protein-inhibitor complex
Function / homology
Function and homology information


parathyroid hormone secretion / TRP channels / calcium-activated cation channel activity / calcium ion import / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium channel activity / calcium ion transmembrane transport / response to calcium ion ...parathyroid hormone secretion / TRP channels / calcium-activated cation channel activity / calcium ion import / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium channel activity / calcium ion transmembrane transport / response to calcium ion / 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 6 / Transient receptor potential cation channel subfamily V member 5/6 / Ankyrin repeats (many copies) / Transient receptor potential cation channel subfamily V / 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 6 / Transient receptor potential cation channel subfamily V member 5/6 / Ankyrin repeats (many copies) / Transient receptor potential cation channel subfamily V / 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
Chem-DTB / 2-aminoethyl (4-bromophenyl)phenylborinate / Transient receptor potential cation channel subfamily V member 6
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.6 Å
AuthorsSingh, A.K. / Saotome, K. / McGoldrick, L.L. / Sobolevsky, A.I.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)1R01CA206573-01A1 United States
CitationJournal: Nat Commun / Year: 2018
Title: Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB.
Authors: Appu K Singh / Kei Saotome / Luke L McGoldrick / Alexander I Sobolevsky /
Abstract: Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its ...Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer. TRPV6 inhibitors suppress tumor growth, but the molecular mechanism of inhibition remains unknown. Here, we present crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle. Comparing human wild-type and high-affinity mutant Y467A structures, we show that 2-APB induces TRPV6 channel closure by modulating protein-lipid interactions. Mutagenesis and functional analyses suggest that the identified 2-APB binding site might be present in other members of vanilloid subfamily TRP channels. Our findings reveal a mechanism of ion channel allosteric modulation that can be exploited for therapeutic design.
History
DepositionApr 25, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 18, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Dec 25, 2024Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_validate_close_contact ...pdbx_entry_details / pdbx_validate_close_contact / struct_conn / struct_conn_type

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,6405
Polymers77,0411
Non-polymers5984
Water00
1
A: Transient receptor potential cation channel subfamily V member 6
hetero molecules

A: Transient receptor potential cation channel subfamily V member 6
hetero molecules

A: Transient receptor potential cation channel subfamily V member 6
hetero molecules

A: Transient receptor potential cation channel subfamily V member 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)310,55920
Polymers308,1664
Non-polymers2,39416
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_445-y-1/2,x-1/2,z1
crystal symmetry operation4_545y+1/2,-x-1/2,z1
Buried area30870 Å2
ΔGint-298 kcal/mol
Surface area103870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.350, 144.350, 113.370
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number90
Space group name H-MP4212
Components on special symmetry positions
IDModelComponents
11A-701-

CA

21A-702-

CA

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Components

#1: Protein Transient receptor potential cation channel subfamily V member 6 / TrpV6 / Calcium transport protein 1 / CaT1 / Epithelial calcium channel 2 / ECaC2


Mass: 77041.398 Da / Num. of mol.: 1 / Mutation: Y466A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Trpv6 / Production host: Homo sapiens (human) / References: UniProt: Q9R186
#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-FYY / 2-aminoethyl (4-bromophenyl)phenylborinate


Mass: 303.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15BBrNO
#4: Chemical ChemComp-DTB / 6-(5-METHYL-2-OXO-IMIDAZOLIDIN-4-YL)-HEXANOIC ACID / D-DESTHIOBIOTIN


Mass: 214.262 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H18N2O3
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.83 Å3/Da / Density % sol: 67.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 20-24% PEG 350 MME, 50 mM NaCl, and 50 mM Tris-HCl pH 8.0-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 6, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 3.6→50 Å / Num. obs: 25909 / % possible obs: 97.7 % / Redundancy: 17 % / Net I/σ(I): 9.41
Reflection shellResolution: 3.6→3.69 Å

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WO7

5wo7


Resolution: 3.6→46.537 Å / SU ML: 0.6 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 36.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3156 1307 5.04 %RANDOM
Rwork0.2822 ---
obs0.2839 25909 97.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.6→46.537 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4773 0 35 0 4808
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034918
X-RAY DIFFRACTIONf_angle_d0.6446675
X-RAY DIFFRACTIONf_dihedral_angle_d13.3822915
X-RAY DIFFRACTIONf_chiral_restr0.038760
X-RAY DIFFRACTIONf_plane_restr0.004843
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.6003-3.74440.42861450.39772757X-RAY DIFFRACTION99
3.7444-3.91480.39631470.36772781X-RAY DIFFRACTION99
3.9148-4.1210.39531460.33442748X-RAY DIFFRACTION99
4.121-4.37910.33761480.28432771X-RAY DIFFRACTION98
4.3791-4.71690.28851470.25722731X-RAY DIFFRACTION98
4.7169-5.1910.28171440.26532751X-RAY DIFFRACTION98
5.191-5.94080.35071460.27182712X-RAY DIFFRACTION97
5.9408-7.47980.27191410.28152696X-RAY DIFFRACTION96
7.4798-46.54130.27771430.25072655X-RAY DIFFRACTION94

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