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Structure paper

TitleStructural bases of TRP channel TRPV6 allosteric modulation by 2-APB.
Journal, issue, pagesNat Commun, Vol. 9, Issue 1, Page 2465, Year 2018
Publish dateJun 25, 2018
AuthorsAppu K Singh / Kei Saotome / Luke L McGoldrick / Alexander I Sobolevsky /
PubMed AbstractTransient 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.
External linksNat Commun / PubMed:29941865 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.37 - 4.44 Å
Structure data

7824

6d7s

EMDB-7824, PDB-6d7s:
Cryo-EM structure of human TRPV6-Y467A in amphipols
Method: EM (single particle) / Resolution: 4.34 Å

7825

6d7t

EMDB-7825, PDB-6d7t:
Cryo-EM structure of human TRPV6-Y467A in complex with 2-Aminoethoxydiphenyl borate (2-APB)
Method: EM (single particle) / Resolution: 4.44 Å

PDB-6d7o:
Crystal Structure of Rat TRPV6* in complex with 2-Aminoethoxydiphenyl borate (2-APB)
Method: X-RAY DIFFRACTION / Resolution: 3.45 Å

PDB-6d7p:
Crystal Structure of Rat TRPV6*-Y466A
Method: X-RAY DIFFRACTION / Resolution: 3.37 Å

PDB-6d7q:
Crystal Structure of Rat TRPV6*-Y466A in complex with 2-Aminoethoxydiphenyl borate (2-APB)
Method: X-RAY DIFFRACTION / Resolution: 3.497 Å

PDB-6d7v:
Crystal Structure of Rat TRPV6*- in complex with brominated 2-Aminoethoxydiphenyl borate (2-APB-Br)
Method: X-RAY DIFFRACTION / Resolution: 4.3 Å

PDB-6d7x:
Crystal Structure of Rat TRPV6*-Y466A- in complex with brominated 2-Aminoethoxydiphenyl borate (2-APB-Br)
Method: X-RAY DIFFRACTION / Resolution: 3.6 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-FZ4:
2-aminoethyl diphenylborinate / 2-Aminoethoxydiphenyl borate

ChemComp-DTB:
6-(5-METHYL-2-OXO-IMIDAZOLIDIN-4-YL)-HEXANOIC ACID

ChemComp-FYY:
2-aminoethyl (4-bromophenyl)phenylborinate

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
Keywordsmembrane protein/inhibitor / Ion channels / transporter / calcium channel / epithelial calcium channel / MEMBRANE PROTEIN / membrane protein-inhibitor complex

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