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- PDB-6d7x: Crystal Structure of Rat TRPV6*-Y466A- in complex with brominated... -
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Open data
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Basic information
Entry | Database: PDB / ID: 6d7x | ||||||
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Title | Crystal Structure of Rat TRPV6*-Y466A- in complex with brominated 2-Aminoethoxydiphenyl borate (2-APB-Br) | ||||||
![]() | Transient receptor potential cation channel subfamily V member 6 | ||||||
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Function / homology | ![]() parathyroid hormone secretion / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Singh, A.K. / Saotome, K. / McGoldrick, L.L. / Sobolevsky, A.I. | ||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 136 KB | Display | ![]() |
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PDB format | ![]() | 103.7 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 7824C ![]() 7825C ![]() 6d7oC ![]() 6d7pC ![]() 6d7qC ![]() 6d7sC ![]() 6d7tC ![]() 6d7vC ![]() 5wo7S S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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1 | ![]()
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Unit cell |
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Components on special symmetry positions |
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Components
#1: Protein | Mass: 77041.398 Da / Num. of mol.: 1 / Mutation: Y466A Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() | ||||
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#2: Chemical | #3: Chemical | ChemComp-FYY / | #4: Chemical | ChemComp-DTB / | |
-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 3.83 Å3/Da / Density % sol: 67.91 % |
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Crystal grow![]() | Temperature: 293 K / Method: vapor diffusion Details: 20-24% PEG 350 MME, 50 mM NaCl, and 50 mM Tris-HCl pH 8.0-8.5 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 6, 2017 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength![]() |
Reflection | Resolution: 3.6→50 Å / Num. obs: 25909 / % possible obs: 97.7 % / Redundancy: 17 % / Net I/σ(I): 9.41 |
Reflection shell | Resolution: 3.6→3.69 Å |
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Processing
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Refinement | Method to determine structure![]() ![]() Starting model: 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
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 3.6→46.537 Å
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Refine LS restraints |
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LS refinement shell |
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