7xev

From Proteopedia

Structure of mTRPV2_2-APB

Structural highlights

7xev is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.27Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TRPV2_MOUSE Calcium-permeable, non-selective cation channel with an outward rectification. Seems to be regulated, at least in part, by IGF-I, PDGF and neuropeptide head activator. May transduce physical stimuli in mast cells. Activated by temperatures higher than 52 degrees Celsius; is not activated by vanilloids and acidic pH.^[1] ^[2]

Publication Abstract from PubMed

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 A using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-beta-cyclodextrin (MbetaCD) as resolved at 2.9 A. 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 A) 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.

Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands.,Su N, Zhen W, Zhang H, Xu L, Jin Y, Chen X, Zhao C, Wang Q, Wang X, Li S, Wen H, Yang W, Guo J, Yang F Nat Chem Biol. 2023 Jan;19(1):72-80. doi: 10.1038/s41589-022-01139-8. Epub 2022 , Sep 26. PMID:36163384^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kanzaki M, Zhang YQ, Mashima H, Li L, Shibata H, Kojima I. Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I. Nat Cell Biol. 1999 Jul;1(3):165-70. PMID:10559903 doi:10.1038/11086
↑ Boels K, Glassmeier G, Herrmann D, Riedel IB, Hampe W, Kojima I, Schwarz JR, Schaller HC. The neuropeptide head activator induces activation and translocation of the growth-factor-regulated Ca(2+)-permeable channel GRC. J Cell Sci. 2001 Oct;114(Pt 20):3599-606. PMID:11707512 doi:10.1242/jcs.114.20.3599
↑ Su N, Zhen W, Zhang H, Xu L, Jin Y, Chen X, Zhao C, Wang Q, Wang X, Li S, Wen H, Yang W, Guo J, Yang F. Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands. Nat Chem Biol. 2023 Jan;19(1):72-80. PMID:36163384 doi:10.1038/s41589-022-01139-8