The structure of a complex of recombinant hirudin and human alpha-thrombin.
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.
Rydel
T J
TJ
Department of Chemistry, Michigan State University, East Lansing 48824.
Ravichandran
K G
KG
Tulinsky
A
A
Bode
W
W
Huber
R
R
Roitsch
C
C
Fenton
J W
JW
D000595:Amino Acid Sequence; D001665:Binding Sites; D006629:Hirudins / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D014961:X-Ray Diffraction
D006629:Hirudins; D011994:Recombinant Proteins; D013917:Thrombin