1uvt
From Proteopedia
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'''BOVINE THROMBIN--BM14.1248 COMPLEX''' | '''BOVINE THROMBIN--BM14.1248 COMPLEX''' | ||
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[[Category: Engh, R A.]] | [[Category: Engh, R A.]] | ||
[[Category: Huber, R.]] | [[Category: Huber, R.]] | ||
| - | [[Category: | + | [[Category: Blood coagulation]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Serine protease]] |
| - | [[Category: | + | [[Category: Thrombin]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:45:09 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 08:45, 3 May 2008
BOVINE THROMBIN--BM14.1248 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
1UVT is a Protein complex structure of sequences from Bos taurus. 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 Page seeded by OCA on Sat May 3 11:45:09 2008
