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Thrombin-hirudin complex

Grtitter, M.G., et al. Crystal structure of the thrombin-hirudin complex a novel mode of serine protease inhibition. EMBO J. 9 2361-2365, 1990. [Pg.220]

Collectively, the direct thrombin inhibitors are prototypically represented by hirudin, the antithrombotic molecule found in the saliva of the medicinal leech (Hirudo medicinalis), This protein is a 65 amino acid molecule that forms a highly stable but noncovalent complex with thrombin (7). With two domains, the NH2-terminal core domain and the COOH-terminal tail, the hirudin molecule inhibits the catalytic site and the anion-binding exosite in a two-step process. The first step is an ionic interaction that leads to a rearrangement of the thrombin-hirudin complex to form a tighter bond that is stoi-chiometrically I I and irreversible. The apolar-binding site may also be involved in hirudin binding. This complex and... [Pg.86]

Karshikov A, Bode W, Tulinsky A, et al. (1992). Electrostatic interactions in the association of proteins An analysis of the thrombin-hirudin complex. Protein Sci. 1 727-735. [Pg.1259]

Rydel T. J., Ravichandran K. G., Tulinsky A., et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990 249,277-80. [Pg.166]

Human thrombin complex with Hirudin variant PDB ID IHXF... [Pg.479]

The allo-Thr hydroxyl oxygen accepts a hydrogen bond from the backbone NH of Gly219. This additional interaction accounts, at least in part, for the increase in affinity when compared to the inhibitor with Leu in this position. Comparison of the crystal structures of thrombin complexed with BMS-183507 and with hirudin reveals that the hirudin residue, Thr2, and the allo-Thr of BMS-183507 interact differently with thrombin. The hirudin Thr2 binds at S2,... [Pg.253]

Hirudin [8001-27-2] is a polypeptide of 66 amino acids found in the salivary gland secretions of the leech Hirudo medicinalis (45). It is a potent inhibitor of thrombin and binds to y-thrombin with a dissociation constant of 0.8 x 10 10 M to 2.0 x 10 14 M. Hirudin forms a stable noncovalent complex with free and bound thrombin completely independent of AT-III. This material has now been cloned and expressed in yeast cells (46,47). Its antigenic potential in humans remains to be established. [Pg.178]

The rate constants for the association of proteins with one another and with other macromolecules are profoundly influenced by the geometry of the interaction and by electrostatic factors. Only a small part of each protein may be involved in the formation of a protein-protein complex, which imposes a bad steric factor on the reaction. Accordingly, protein-protein association rate constants may be as low as 104 s 1 M x (Table 4.1). But there is very fast association at > 5 X 109 s-1 AT 1 at low ionic strength for proteins that have complementary charged surfaces, such as bamase with its polypeptide inhibitor barstarfwhose, properties are discussed in Chapter 19), thrombin with its polypeptide inhibitor hirudin, and ferricytochrome c with ferrocytochrome b5. [Pg.417]

TJ Rydel, A Tulinsky, W Bode, R Huber. Refined structure of the hirudin-thrombin complex. J Mol Biol 221 583-601, 1991. [Pg.533]

A 20 amino acid polypeptide [1], bivalirudin (hirulog) is a synthetic version of hirudin. Its amino-terminal D-Phe-Pro-Arg-Pro domain, which interacts with the active site of thrombin, is linked via four Gly residues to a dodecapeptide analogue of the carboxy-terminal of hirudin. Like hirudin, bivalirudin also forms a 1 1 stoichiometric complex with thrombin. Once bound, however, the Arg-Pro bond at the amino-terminal of bivalirudin is cleaved by thrombin, thereby restoring active site functions of the enzyme complexes of a-thrombin [2]. [Pg.644]

Hirudin, a polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicalis, is now produced by recombinant technology. It is a potent and specific inhibitor of thrombin with which it forms an almost irreversible complex. It is cleared predominantly by the kidneys and has a of 40 minutes after i.v. administration. No antidote is available for a bleeding patient. It has been used successfully in patients with heparin-induced thrombocytopenia (HIT), thromboprophylaxis in elective hip arthroplasty, xmstable angina and myocardial infarction. [Pg.577]

X-ray analysis of thrombin complexed by recombinant hirudin showed that this inhibitor binds to two distinct sites of the protease - that is, the amino-terminal tet-rapeptide to the active site, and the C-ter-minal tail (hirudin residues 53-65) to the fibrinogen recognition site (FRE) [32, 93]. This heterobivalent binding mode explains the extremely high affinity and selectivity of hirudin, with a Ki of 21 fM [94]. De-... [Pg.418]


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See also in sourсe #XX -- [ Pg.149 ]

See also in sourсe #XX -- [ Pg.41 ]




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Thrombin hirudin

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