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The crystal structure of α-thrombin-hirunorm IV complex reveals a novel specificity site recognition mode

Published online by Cambridge University Press:  01 January 1999

ANGELA LOMBARDI ,
GIUSEPPINA DE SIMONE ,
FLAVIA NASTRI ,
STEFANIA GALDIERO ,
ROSSELLA DELLA MORTE ,
NORMA STAIANO ,
CARLO PEDONE ,
MARTINO BOLOGNESI  and
VINCENZO PAVONE
ANGELA LOMBARDI
Affiliation:
Centro Interuniversitario di Ricerca su Peptidi Bioattivi & Centro di Studio di Biocristallografia-CNR, University of Napoli “Federico II”, via Mezzocannone 4, 80134 Napoli, Italy
GIUSEPPINA DE SIMONE
Affiliation:
Centro Interuniversitario di Ricerca su Peptidi Bioattivi & Centro di Studio di Biocristallografia-CNR, University of Napoli “Federico II”, via Mezzocannone 4, 80134 Napoli, Italy
FLAVIA NASTRI
Affiliation:
Centro Interuniversitario di Ricerca su Peptidi Bioattivi & Centro di Studio di Biocristallografia-CNR, University of Napoli “Federico II”, via Mezzocannone 4, 80134 Napoli, Italy
STEFANIA GALDIERO
Affiliation:
Centro Interuniversitario di Ricerca su Peptidi Bioattivi & Centro di Studio di Biocristallografia-CNR, University of Napoli “Federico II”, via Mezzocannone 4, 80134 Napoli, Italy
ROSSELLA DELLA MORTE
Affiliation:
Dipartimento di Biochimica e Biotecnologie Mediche, University of Napoli “Federico II”, via Pansini 5, 80129 Napoli, Italy
NORMA STAIANO
Affiliation:
Dipartimento di Biochimica e Biotecnologie Mediche, University of Napoli “Federico II”, via Pansini 5, 80129 Napoli, Italy
CARLO PEDONE
Affiliation:
Centro Interuniversitario di Ricerca su Peptidi Bioattivi & Centro di Studio di Biocristallografia-CNR, University of Napoli “Federico II”, via Mezzocannone 4, 80134 Napoli, Italy
MARTINO BOLOGNESI
Affiliation:
Dipartimento di Genetica e Microbiologia, University of Pavia, Via Abbiategrasso 207, 27100 Pavia, Italy Department of Physics INFM and Advanced Biotechnology Center IST, University of Genova, Largo Rosanna Benzi, 10, 16132 Genova, Italy
VINCENZO PAVONE
Affiliation:
Centro Interuniversitario di Ricerca su Peptidi Bioattivi & Centro di Studio di Biocristallografia-CNR, University of Napoli “Federico II”, via Mezzocannone 4, 80134 Napoli, Italy
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Abstract

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"-2Nal3" (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 2Nal3" 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.

Keywords

bifunctional synthetic thrombin inhibitorscrystal structurehirunormsretro-binding peptides
Type
Research Article
Information
Protein Science , Volume 8 , Issue 1 , January 1999 , pp. 91 - 95
Copyright
© 1999 The Protein Society

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