The crystal structure of alpha-thrombin-hinunorm IV complex reveals a novel specificity site recognition mode(212 views visite) Lombardi A, De Simone G, Nastri F, Galdiero S, Della Morte R, Staiano N, Pedone C, Bolognesi M, Pavone V
Protein Sci (ISSN: 0961-8368, 1469-896xelectronic), 1999 Jan; 8(1): N/D-N/D.
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The crystal structure of alpha-thrombin-hinunorm IV complex reveals a novel specificity site recognition mode
The X-ray crystal structure of the human alpha-thrombin-hirunorm IV complex has been determined at 2.5 Angstrom 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 "-2Nal3 " (Chg, cyclohexyl-glycine; 2Nal, 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.
The crystal structure of alpha-thrombin-hinunorm IV complex reveals a novel specificity site recognition mode
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