6WKN

PL-bound rat TRPV2 in nanodiscs

Summary for 6WKN

• Entry DOI: 10.2210/pdb6wkn/pdb
• EMDB information: 21705
• Descriptor: Transient receptor potential cation channel subfamily V member 2, piperlongumine (2 entities in total)
• Functional Keywords: trp channel, trpv2, piperlongumine, ion channel, transport protein
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 4
• Total formula weight: 348464.91

Authors

Pumroy, R.P.,Moiseenkova-Bell, V.Y. (deposition date: 2020-04-16, release date: 2021-04-21, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.46 Å)