Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 6, Pages 1832-1837Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710894105
Keywords
protease activated receptor; thrombin; x-ray crystallography
Categories
Funding
- NHLBI NIH HHS [R01 HL058141, R29 HL049413, R01 HL049413, HL58141, R01 HL073813, HL49413, HL73813] Funding Source: Medline
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Allostery is a common mechanism of regulation of enzyme activity and specificity, and its signatures are readily identified from functional studies. For many allosteric systems, structural evidence exists of long-range communication among protein domains, but rarely has this communication been traced to a detailed pathway. The thrombin mutant D102N is stabilized in a self-inhibited conformation where access to the active site is occluded by a collapse of the entire 215-219 beta-strand. Binding of a fragment of the protease activated receptor PARI to exosite 1, 30-angstrom away from the active site region, causes a large conformational change that corrects the position of the 215-219 beta-strand and restores access to the active site. The crystal structure of the thrombin-PAR1 complex, solved at 2.2-angstrom resolution, reveals the details of this long-range allosteric communication in terms of a network of polar interactions.
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