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Structure of the Adenosine A2A Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine
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SUMMARY Methylxanthines, including caffeine and theophylline are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogues with improved properties have been developed as potential treatments for diseases such as Parkinson’s disease. Here we report the structures of a thermostabilised adenosine A2A receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A2A selective inverse agonist ZM241385. The receptor is crystallised in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features which define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions which interact with signal transduction proteins.
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Metadata
- Authors
- Doré, A. S., Robertson, N., Errey, J. C., Ng, I., Hollenstein, K., Tehan, B., Hurrell, E., Bennett, K., Congreve, M., Magnani, F., Tate, C. G., Weir, M., & Marshall, F. H.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 19
- Issue
- 9
- Pages
- 1283-1293
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2142322475
- Cited by
- 553
- References
- 50
- FWCI
- 19.28
- Type
- journal article
- Language
- en
- Open access
- bronze
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