The Crystal Structure Of Alpha-Thrombin-Hirunorm Iv Complex Reveals A Novel Specificity Site Recognition Mode(444 views) 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): 91-95.
Affiliations: Ctro. Interuniversitario Ric. P., University of Napoli Federico II, via Mezzocannone 4, 80134 Napoli, Italy
Dipto. Biochim. Biotecnologie M., University of Napoli Federico II, via Pansini 5, 80129 Napoli, Italy
Dipto. di Genetica e Microbiologia, University of Pavia, via Abbiategrasso 207, 27100 Pavia, Italy
Dept. Phys. INFM Adv. Biotech. C., University of Genova, Largo Rosanna Benzi, 10, 16132 Genova, Italy
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The Crystal Structure Of Alpha-Thrombin-Hirunorm Iv Complex Reveals A Novel Specificity Site Recognition Mode
The X-ray crystal structure of the human α-thrombin-hirunorm IV complex has been determined at 2.5 Å 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 α-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; 2Nal, β-(2-naphthyl)-alanine) forms a parallel β-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-Hirunorm Iv Complex Reveals A Novel Specificity Site Recognition Mode