1uvu

From Proteopedia

Revision as of 02:13, 21 November 2007

BOVINE THROMBIN--BM12.1700 COMPLEX

Overview

BACKGROUND: The explosive growth in the rate of X-ray determination of, protein structures is fuelled largely by the expectation that structural, information will be useful for pharmacological and biotechnological, applications. For example, there have been intensive efforts to develop, orally administrable antithrombotic drugs using information about the, crystal structures of blood coagulation factors, including thrombin. Most, of the low molecular weight thrombin inhibitors studied so far are based, on arginine and benzamidine. We sought to expand the database of, information on thrombin-inhibitor binding by studying new classes of, inhibitors. RESULTS: We report the structures of three new inhibitors, complexed with thrombin, two based on 4-aminopyridine and one based on, naphthamidine. We observe several geometry changes in the protein main, chain and side chains which accompany inhibitor binding. The two, inhibitors based on 4-aminopyridine bind in notably different ways: one, forms a water-mediated hydrogen bond to the active site Ser195, the other, induces a rotation of the Ser214-Trp215 peptide plane that is, unprecedented in thrombin structures. These binding modes also differ in, their 'weak' interactions, including CH-O hydrogen bonds and interactions, between water molecules and aromatic pi-clouds. Induced-fit structural, changes were also seen in the structure of the naphthamidine inhibitor, complex. CONCLUSIONS: Protein flexibility and variable water structures, are essential elements in protein-ligand interactions. Ligand design, strategies that fail to take this into account may overlook or, underestimate the potential of lead structures. Further, the significance, of 'weak' interactions must be considered both in crystallographic, refinement and in analysis of binding mechanisms.

About this Structure

1UVU is a Protein complex structure of sequences from Bos taurus with DCH as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

Enzyme flexibility, solvent and 'weak' interactions characterize thrombin-ligand interactions: implications for drug design., Engh RA, Brandstetter H, Sucher G, Eichinger A, Baumann U, Bode W, Huber R, Poll T, Rudolph R, von der Saal W, Structure. 1996 Nov 15;4(11):1353-62. PMID:8939759

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