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Tick saliva contains potent antihemostatic molecules that help ticks obtain their enormous blood meal during prolonged feeding. We isolated thrombin inhibitors present in the salivary gland extract from partially fed female Amblyomma variegatum, the tropical bont tick, and characterized the most potent, variegin, one of the smallest (32 residues) thrombin inhibitors found in nature. Full-length variegin and two truncated variants were chemically synthesized. Despite its small size and flexible structure, variegin binds thrombin with strong affinity (K(i) approximately 10.4 pM) and high specificity. Results using the truncated variants indicated that the seven residues at the N terminus affected the binding kinetics; when removed, the binding characteristics changed from fast to slow. Further, the thrombin active site binding moiety of variegin is in the region of residues 8-14, and the exosite-I binding moiety is within residues 15-32. Our results show that variegin is structurally and functionally similar to the rationally designed thrombin inhibitor, hirulog. However, compared with hirulog, variegin is a more potent inhibitor, and its inhibitory activity is largely retained after cleavage by thrombin.

Original publication

DOI

10.1074/jbc.M705600200

Type

Journal article

Journal

J Biol Chem

Publication Date

05/10/2007

Volume

282

Pages

29101 - 29113

Keywords

Amino Acid Sequence, Animals, Circular Dichroism, Female, Humans, Kinetics, Models, Chemical, Molecular Sequence Data, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Salivary Glands, Salivary Proteins and Peptides, Serine, Thrombin, Ticks