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Title | Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands. |
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Journal, issue, pages | Nat Chem Biol, Vol. 19, Issue 1, Page 72-80, Year 2023 |
Publish date | Sep 26, 2022 |
Authors | Nannan Su / Wenxuan Zhen / Heng Zhang / Lingyi Xu / Yitian Jin / Xiaoying Chen / Cheng Zhao / Qinrui Wang / Xinyan Wang / Shaowei Li / Han Wen / Wei Yang / Jiangtao Guo / Fan Yang / |
PubMed Abstract | The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being ...The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being identified, whether and how TRPV2 is regulated by endogenous lipids remains elusive. Here, we report an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2, with a 'head down, tail up' configuration, resolved at 3.2 Å using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-β-cyclodextrin (MβCD) as resolved at 2.9 Å. We also observed that estradiol (E2) potentiated TRPV2 activation by 2-aminoethoxydiphenyl borate (2-APB), a classic tool compound for TRP channels. Our cryo-EM structures (resolved at 2.8-3.3 Å) further suggest how E2 disturbed cholesterol binding and how 2-APB bound within the VBP with E2 or without both E2 and endogenous cholesterol, respectively. Therefore, our study has established the structural basis for ligand recognition of the inhibitory endogenous cholesterol and excitatory exogenous 2-APB in TRPV2. |
External links | Nat Chem Biol / PubMed:36163384 |
Methods | EM (single particle) |
Resolution | 2.47 - 3.27 Å |
Structure data | EMDB-33156, PDB-7xem: EMDB-33157, PDB-7xeo: EMDB-33158, PDB-7xer: EMDB-33159, PDB-7xeu: EMDB-33160, PDB-7xev: EMDB-33161, PDB-7xew: EMDB-33774, PDB-7yep: |
Chemicals | ChemComp-CLR: ChemComp-HOH: ChemComp-FZ4: |
Source |
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Keywords | STRUCTURAL PROTEIN / mTRPV2 / chloesterol / MbetaCD / MEMBRANE PROTEIN / 2-APB |