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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]] 1.90&Aring;' scene=''>
<StructureSection load='1f28' size='340' side='right'caption='[[1f28]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1f28]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Pneca Pneca]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F28 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1F28 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1f28]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F28 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1F28 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F89:S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC+ACID'>F89</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ci7|1ci7]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F89:S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC+ACID'>F89</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=1f28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1f28 OCA], [https://pdbe.org/1f28 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1f28 RCSB], [https://www.ebi.ac.uk/pdbsum/1f28 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1f28 ProSAT]</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>
== Function ==
[https://www.uniprot.org/uniprot/TYSY_PNECA TYSY_PNECA]
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1f28 ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1f28 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


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<ref>PMID:11358692</ref>
==See Also==
 
*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1f28" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Pneca]]
[[Category: Large Structures]]
[[Category: Thymidylate synthase]]
[[Category: Pneumocystis carinii]]
[[Category: Anderson, A C]]
[[Category: Anderson AC]]
[[Category: Neil, R H.O]]
[[Category: O'Neil RH]]
[[Category: Stroud, R M]]
[[Category: Stroud RM]]
[[Category: Surti, T S]]
[[Category: Surti TS]]
[[Category: Beta-sheet]]
[[Category: Protein-inhibitor complex]]
[[Category: Transferase]]

Latest revision as of 13:09, 20 March 2024

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

1f28 is a 4 chain structure with sequence from Pneumocystis carinii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TYSY_PNECA

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

1f28, resolution 1.90Å

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