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- EMDB-7825: Cryo-EM structure of human TRPV6-Y467A in complex with 2-Aminoeth... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-7825 | |||||||||
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Title | Cryo-EM structure of human TRPV6-Y467A in complex with 2-Aminoethoxydiphenyl borate (2-APB) | |||||||||
![]() | primary map | |||||||||
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Function / homology | ![]() parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport ...parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport / calmodulin binding / identical protein binding / metal ion binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.44 Å | |||||||||
![]() | Singh AK / Saotome K / McGoldrick LL / Sobolevsky AI | |||||||||
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
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 3.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 11.9 KB 11.9 KB | Display Display | ![]() |
Images | ![]() | 241 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6d7tMC ![]() 7824C ![]() 6d7oC ![]() 6d7pC ![]() 6d7qC ![]() 6d7sC ![]() 6d7vC ![]() 6d7xC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | primary map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.22 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : TRPV6 in amphipols
Entire | Name: TRPV6 in amphipols |
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Components |
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-Supramolecule #1: TRPV6 in amphipols
Supramolecule | Name: TRPV6 in amphipols / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Transient receptor potential cation channel subfamily V member 6
Macromolecule | Name: Transient receptor potential cation channel subfamily V member 6 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 85.076859 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPLL LAAKDNDVQA LNKLLKYEDC KVHQRGAMGE TALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT ALHIAVVNQN MNLVRALLAR RASVSARATG TAFRRSPCNL I YFGEHPLS ...String: MGLSLPKEKG LILCLWSKFC RWFQRRESWA QSRDEQNLLQ QKRIWESPLL LAAKDNDVQA LNKLLKYEDC KVHQRGAMGE TALHIAALY DNLEAAMVLM EAAPELVFEP MTSELYEGQT ALHIAVVNQN MNLVRALLAR RASVSARATG TAFRRSPCNL I YFGEHPLS FAACVNSEEI VRLLIEHGAD IRAQDSLGNT VLHILILQPN KTFACQMYNL LLSYDRHGDH LQPLDLVPNH QG LTPFKLA GVEGNTVMFQ HLMQKRKHTQ WTYGPLTSTL YDLTEIDSSG DEQSLLELII TTKKREARQI LDQTPVKELV SLK WKRYGR PYFCMLGAIY LLYIICFTMC CIYRPLKPRT NNRTSPRDNT LLQQKLLQEA YMTPKDDIRL VGELVTVIGA IIIL LVEVP DIFRMGVTRF FGQTILGGPF HVLIITYAFM VLVTMVMRLI SASGEVVPMS FALVLGWCNV MAFARGFQML GPFTI MIQK MIFGDLMRFC WLMAVVILGF ASAFYIIFQT EDPEELGHFY DYPMALFSTF ELFLTIIDGP ANYNVDLPFM YSITYA AFA IIATLLMLNL LIAMMGDTHW RVAHERDELW RAQIVATTVM LERKLPRCLW PRSGICGREY GLGDRWFLRV EDRQDLN RQ RIQRYAQAFH TRGSEDLDKD SVEKLELGCP FSPHLSLPMP SVSRSTSRSS ANWERLRQGT LRRDLRGIIN RGLEDGES W EYQILVPRGS AAAWSHPQFE K |
-Macromolecule #2: 2-aminoethyl diphenylborinate
Macromolecule | Name: 2-aminoethyl diphenylborinate / type: ligand / ID: 2 / Number of copies: 4 / Formula: FZ4 |
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Molecular weight | Theoretical: 225.094 Da |
Chemical component information | ![]() ChemComp-FZ4: |
-Macromolecule #3: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.5 mg/mL | |||||||||
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Buffer | pH: 8 Component:
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Grid | Material: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K |
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Electron microscopy
Microscope | FEI TECNAI 20 |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 43.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: ![]() |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD |
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Image processing
Startup model | Type of model: EMDB MAP EMDB ID: |
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Final reconstruction | Number classes used: 1 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 4.44 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 77460 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |