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Structural basis for subtype-specific inhibition of the P2X7 receptor
Open accessAbstract
The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.
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Cited by
The P2X7 Receptor in Infection and Inflammation
Di Virgilio, F., Dal Ben, D., Sarti, A. C., Giuliani, A. L., & Falzoni, S. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.020 · Cited by 1,267
Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential
Inoue, K., & Tsuda, M. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.2 · Cited by 908
The P2X7 receptor: A main player in inflammation
Adinolfi, E., Giuliani, A. L., De Marchi, E., Pegoraro, A., Orioli, E., & Di Virgilio, F. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.12.021 · Cited by 385
Purine Release, Metabolism, and Signaling in the Inflammatory Response
Linden, J., Koch-Nolte, F., & Dahl, G. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052406 · Cited by 377
Update of P2X receptor properties and their pharmacology: IUPHAR Review 30
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Metadata
- Authors
- Karasawa, A., & Kawate, T.
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-12-09
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W2559826741
- Cited by
- 303
- References
- 9
- FWCI
- 19.38
- Type
- journal article
- Language
- en
- Open access
- gold
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
