1f28
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(New page: 200px<br /><applet load="1f28" size="450" color="white" frame="true" align="right" spinBox="true" caption="1f28, resolution 1.90Å" /> '''CRYSTAL STRUCTURE OF...)
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Revision as of 12:25, 20 November 2007
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CRYSTAL STRUCTURE OF THYMIDYLATE SYNTHASE FROM PNEUMOCYSTIS CARINII BOUND TO DUMP AND BW1843U89
Overview
BACKGROUND: Using fixed receptor sites derived from high-resolution, crystal structures in structure-based drug design does not properly, account for ligand-induced enzyme conformational change and imparts a bias, into the discovery and design of novel ligands. We sought to facilitate, the design of improved drug leads by defining residues most likely to, change conformation, and then defining a minimal manifold of possible, conformations of a target site for drug design based on a small number of, identified flexible residues. RESULTS: The crystal structure of, thymidylate synthase from an important pathogenic target Pneumocystis, carinii (PcTS) bound to its substrate and the inhibitor, BW1843U89, is, reported here and reveals a new conformation with respect to the structure, of PcTS bound to substrate and the more conventional antifolate inhibitor, CB3717. We developed an algorithm for determining which residues provide, 'soft spots' in the protein, regions where conformational adaptation, suggests possible modifications for a drug lead that may yield higher, affinity. Remodeling the active site of thymidylate synthase with new, conformations for only three residues that were identified with this, algorithm yields scores for ligands that are compatible with experimental, kinetic data. CONCLUSIONS: Based on the examination of many protein/ligand, complexes, we develop an algorithm (SOFTSPOTS) for identifying regions of, a protein target that are more likely to accommodate plastically to, regions of a drug molecule. Using these indicators we develop a second, algorithm (PLASTIC) that provides a minimal manifold of possible, conformations of a protein target for drug design, reducing the bias in, structure-based drug design imparted by structures of enzymes, co-crystallized with inhibitors.
About this Structure
1F28 is a Single protein structure of sequence from Pneumocystis carinii with UMP and F89 as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
Reference
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking., Anderson AC, O'Neil RH, Surti TS, Stroud RM, Chem Biol. 2001 May;8(5):445-57. PMID:11358692
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