6WKN

PL-bound rat TRPV2 in nanodiscs

6WKN の概要

• エントリーDOI: 10.2210/pdb6wkn/pdb
• EMDBエントリー: 21705
• 分子名称: Transient receptor potential cation channel subfamily V member 2, piperlongumine (2 entities in total)
• 機能のキーワード: trp channel, trpv2, piperlongumine, ion channel, transport protein
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 348464.91

構造登録者

Pumroy, R.P.,Moiseenkova-Bell, V.Y. (登録日: 2020-04-16, 公開日: 2021-04-21, 最終更新日: 2024-03-06)

主引用文献

Conde, J.,Pumroy, R.A.,Baker, C.,Rodrigues, T.,Guerreiro, A.,Sousa, B.B.,Marques, M.C.,de Almeida, B.P.,Lee, S.,Leites, E.P.,Picard, D.,Samanta, A.,Vaz, S.H.,Sieglitz, F.,Langini, M.,Remke, M.,Roque, R.,Weiss, T.,Weller, M.,Liu, Y.,Han, S.,Corzana, F.,Morais, V.A.,Faria, C.C.,Carvalho, T.,Filippakopoulos, P.,Snijder, B.,Barbosa-Morais, N.L.,Moiseenkova-Bell, V.Y.,Bernardes, G.J.L.
Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.
Acs Cent.Sci., 7:868-881, 2021

PubMed Abstract: The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL . Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.

PubMed: 34079902
DOI: 10.1021/acscentsci.1c00070

実験手法

ELECTRON MICROSCOPY (3.46 Å)