Crystal structure of human alpha-thrombin complexed with hirugen and p-amidinophenylpyruvate at 1.6 A resolution
Research article published in Archives of biochemistry and biophysics (1995)
Abstract
Crystals of human alpha-thrombin complexed with hirugen and the alpha-keto acid thrombin inhibitor APPA (p-amidinophenylpyruvate) that diffract to 1.6 A resolution were obtained by soaking an alpha-thrombin-hirugen crystal in a solution of APPA. The crystal structure was determined using the difference Fourier method and refined to an R factor of 18.7% at 1.6 A resolution. This structure is the highest resolution structure of the thrombin molecule that is currently available. With the exception of the region near Arg77A-Asn78, the structures of the thrombin and hirugen molecules in the ternary complex are similar to those reported for the thrombin-hirugen binary complex. As previously determined for the APPA-trypsin complex, the carbonyl carbon atom of APPA forms a covalent bond with O gamma of Ser195 of thrombin to yield a "transition-state" analog of the tetrahedral intermediate. Comparison of the specificity pocket of the APPA complexes of thrombin and trypsin reveals differences in hydrogen bonding and shows for the first time that the S1 site of thrombin is larger than that of trypsin and as a result thrombin may be able to accommodate a bulkier P1 group than trypsin.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Crystals of human alpha-thrombin complexed with hirugen and the alpha-keto acid thrombin inhibitor APPA (p-amidinophenylpyruvate) that diffract to 1.6 A resolution were obtained by soaking an alpha-thrombin-hirugen crystal in a solution of APPA.
Por qué esto importa para la hirudoterapia
Este artículo describe la estructura cristalina a resolución de 1,6 Å de la alfa-trombina humana en complejo con hirugen y APPA (p-amidinofenilpiruvato), comunicada como la estructura de trombina de mayor resolución disponible actualmente. El resumen indica que las moléculas de trombina e hirugen en el complejo ternario son similares a las comunicadas para el complejo binario trombina-hirugen, describe el enlace covalente entre APPA y Ser195 como un análogo del estado de transición, y compara los bolsillos de especificidad de la trombina y la tripsina mostrando que el sitio S1 de la trombina es más grande. Para ASH, la relevancia es indirecta: hirugen es un componente nombrado del complejo, aunque el resumen no especifica su origen ni su relación estructural con la hirudina. La advertencia es que el estudio es puramente cristalográfico/in vitro sin datos terapéuticos ni in vivo.
Citación
Crystal structure of human alpha-thrombin complexed with hirugen and p-amidinophenylpyruvate at 1.6 A resolution
Chen Z et al. · Archives of biochemistry and biophysics, 1995
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: 18 de junio de 2026