The crystal structure of alpha-thrombin-hirunorm IV complex reveals a novel specificity site recognition mode
Research article published in Protein science : a publication of the Protein Society (1999)
Abstract
The X-ray crystal structure of the human alpha-thrombin-hirunorm IV complex has been determined at 2.5 A resolution, and refined to an R-factor of 0.173. The structure reveals an inhibitor binding mode distinctive of a true hirudin mimetic, which justifies the high inhibitory potency and the selectivity of hirunorm IV. This novel inhibitor, composed of 26 amino acids, interacts through the N-terminal end with the alpha-thrombin active site in a nonsubstrate mode, and binds specifically to the fibrinogen recognition exosite through the C-terminal end. The backbone of the N-terminal tripeptide Chg1"-Arg2"-2Na13" (Chg, cyclohexyl-glycine; 2Na1, beta-(2-naphthyl)-alanine) forms a parallel beta-strand to the thrombin main-chain segment Ser214-Gly216. The Chg1" side chain occupies the S2 site, Arg2" penetrates into the S1 specificity site, while the 2Na13" side chain occupies the aryl binding site. The Arg2" side chain enters the S1 specificity pocket from a position quite apart from the canonical P1 site. This notwithstanding, the Arg2" side chain establishes the typical ion pair with the carboxylate group of Asp189.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
The X-ray crystal structure of the human alpha-thrombin-hirunorm IV complex has been determined at 2.5 A resolution, and refined to an R-factor of 0.173.
Por qué esto importa para la hirudoterapia
This article presents the 2.5 Å crystal structure of the human alpha-thrombin–hirunorm IV complex, refined to an R-factor of 0.173. The abstract describes hirunorm IV as a novel 26-amino-acid inhibitor whose binding mode is distinctive of a true hirudin mimetic, interacting through its N-terminal end with the thrombin active site in a nonsubstrate mode and binding to the fibrinogen recognition exosite through its C-terminal end. The structure reveals that Arg2" enters the S1 specificity pocket from a noncanonical position while still forming the typical ion pair with Asp189. For ASH, the relevance is that hirunorm IV is described in the abstract as a true hirudin mimetic, structurally characterized in complex with thrombin. The caveat is that the study is purely crystallographic, and the abstract provides no in-vivo or therapeutic data.
Citación
The crystal structure of alpha-thrombin-hirunorm IV complex reveals a novel specificity site recognition mode
Lombardi A et al. · Protein science : a publication of the Protein Society, 1999
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: June 18, 2026