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The crystal structure of α‐thrombin‐hirunorm IV complex reveals a novel specificity site recognition mode
Author(s) -
Lombardi Angela,
Simone Giuseppina De,
Nastri Flavia,
Galdiero Stefania,
Pedone Carlo,
Pavone Vincenzo,
Morte Rossella Della,
Staiano Norma,
Bolognesi Martino
Publication year - 1999
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.8.1.91
Subject(s) - tripeptide , stereochemistry , chemistry , thrombin , binding site , side chain , hirudin , active site , alanine , protein structure , amino acid , biochemistry , enzyme , biology , platelet , organic chemistry , immunology , polymer
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.