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Science 20 July 1990:
Vol. 249. no. 4966, pp. 277 - 280
DOI: 10.1126/science.2374926
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Articles
Science, Vol 249, Issue 4966, 277-280
Copyright © 1990 by American Association for the Advancement of Science
The structure of a complex of recombinant hirudin and human alpha-thrombin
TJ Rydel,
KG Ravichandran,
A Tulinsky,
W Bode,
R Huber,
C Roitsch,
and
JW Fenton 2nd
Department of Chemistry, Michigan State University, East Lansing 48824.
The crystallographic structure of a recombinant hirudin-thrombin complex has been solved at 2.3 angstrom (A) resolution. Hirudin consists of an NH2-terminal globular domain and a long (39 A) COOH-terminal extended domain. Residues Ile1 to Tyr3 of hirudin form a parallel beta-strand with Ser214 to Glu217 of thrombin with the nitrogen atom of Ile1 making a hydrogen bond with Ser195 O gamma atom of the catalytic site, but the specificity pocket of thrombin is not involved in the interaction. The COOH-terminal segment makes numerous electrostatic interactions with an anion-binding exosite of thrombin, whereas the last five residues are in a helical loop that forms many hydrophobic contacts. In all, 27 of the 65 residues of hirudin have contacts less than 4.0 A with thrombin (10 ion pairs and 23 hydrogen bonds). Such abundant interactions may account for the high affinity and specificity of hirudin.
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