The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
High-resolution crystal structure of human protease-activated receptor 1
Open accessAbstract
Protease-activated receptor 1 (PAR1) is the prototypical member of a family of G-protein-coupled receptors that mediate cellular responses to thrombin and related proteases. Thrombin irreversibly activates PAR1 by cleaving the amino-terminal exodomain of the receptor, which exposes a tethered peptide ligand that binds the heptahelical bundle of the receptor to affect G-protein activation. Here we report the 2.2-Å-resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated G-protein-coupled receptors, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent. Protease-activated receptors are important targets for drug development. The structure reported here will aid the development of improved PAR1 antagonists and the discovery of antagonists to other members of this receptor family.
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Metadata
- Authors
- Zhang, C., Srinivasan, Y., Arlow, D. H., Fung, J. J., Palmer, D., Zheng, Y., Green, H. F., Pandey, A., Dror, R. O., Shaw, D. E., Weis, W. I., Coughlin, S. R., & Kobilka, B. K.
- Venue
- Nature
- Published
- 2012-12
- Volume
- 492
- Issue
- 7429
- Pages
- 387-392
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2035369931
- Cited by
- 455
- References
- 11
- FWCI
- 18.94
- Type
- journal article
- Language
- en
- Open access
- green
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- Zhang, C., Srinivasan, Y., Arlow, D. H., Fung, J. J., Palmer, D., Zheng, Y., Green, H. F., Pandey, A., Dror, R. O., Shaw, D. E., Weis, W. I., Coughlin, S. R., & Kobilka, B. K. (2012). High-resolution crystal structure of human protease-activated receptor 1. Nature. https://doi.org/10.1038/nature11701
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