Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition
Research article published in The EMBO journal (1990)
Abstract
Thrombin is a serine protease that plays a central role in blood coagulation. It is inhibited by hirudin, a polypeptide of 65 amino acids, through the formation of a tight, noncovalent complex. Tetragonal crystals of the complex formed between human alpha-thrombin and recombinant hirudin (variant 1) have been grown and the crystal structure of this complex has been determined to a resolution of 2.95 A. This structure shows that hirudin inhibits thrombin by a previously unobserved mechanism. In contrast to other inhibitors of serine proteases, the specificity of hirudin is not due to interaction with the primary specificity pocket of thrombin, but rather through binding at sites both close to and distant from the active site. The carboxyl tail of hirudin (residues 48-65) wraps around thrombin along the putative fibrinogen secondary binding site. This long groove extends from the active site cleft and is flanked by the thrombin loops 35-39 and 70-80. Hirudin makes a number of ionic and hydrophobic interactions with thrombin in this area. Furthermore hirudin binds with its N-terminal three residues Val, Val, Tyr to the thrombin active site cleft. Val1 occupies the position P2 and Tyr3 approximately the position P3 of the synthetic inhibitor D-Phe-Pro-ArgCH2Cl. Thus the hirudin polypeptide chain runs in a direction opposite to that expected for fibrinogen and that observed for the substrate-like inhibitor D-Phe-Pro-ArgCH2Cl.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Thrombin is a serine protease that plays a central role in blood coagulation.
Por qué esto importa para la hirudoterapia
Este estudio determinó la estructura cristalográfica del complejo formado entre la alfa-trombina humana y la hirudina recombinante (variante 1) a una resolución de 2,95 Å. El resumen describe la hirudina como un polipéptido de 65 aminoácidos que inhibe la trombina mediante un mecanismo novedoso: en lugar de interactuar con el bolsillo de especificidad primaria, la hirudina se une en sitios tanto próximos como distantes al sitio activo, con su extremo C-terminal envolviendo el sitio de unión secundario del fibrinógeno y sus residuos N-terminales ocupando la hendidura del sitio activo. Este trabajo estructural es relevante para comprender la inhibición de la trombina a nivel molecular. No obstante, el resumen no menciona sanguijuelas, saliva de sanguijuela ni sanguijuelas medicinales, y se trata de un estudio preclínico de biología estructural sin aplicación directa a la terapia con sanguijuelas vivas.
Citación
Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition
Grtter MG et al. · The EMBO journal, 1990
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026