1f28: Difference between revisions
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==CRYSTAL STRUCTURE OF THYMIDYLATE SYNTHASE FROM PNEUMOCYSTIS CARINII BOUND TO DUMP AND BW1843U89== | ==CRYSTAL STRUCTURE OF THYMIDYLATE SYNTHASE FROM PNEUMOCYSTIS CARINII BOUND TO DUMP AND BW1843U89== | ||
<StructureSection load='1f28' size='340' side='right' caption='[[1f28]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='1f28' size='340' side='right' caption='[[1f28]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ci7|1ci7]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ci7|1ci7]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1f28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1f28 OCA], [http://pdbe.org/1f28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1f28 RCSB], [http://www.ebi.ac.uk/pdbsum/1f28 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1f28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1f28 OCA], [http://pdbe.org/1f28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1f28 RCSB], [http://www.ebi.ac.uk/pdbsum/1f28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1f28 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
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Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f2/1f28_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f2/1f28_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
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</div> | </div> | ||
<div class="pdbe-citations 1f28" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 1f28" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 10:09, 20 December 2017
CRYSTAL STRUCTURE OF THYMIDYLATE SYNTHASE FROM PNEUMOCYSTIS CARINII BOUND TO DUMP AND BW1843U89CRYSTAL STRUCTURE OF THYMIDYLATE SYNTHASE FROM PNEUMOCYSTIS CARINII BOUND TO DUMP AND BW1843U89
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References |
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