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| | ==E. coli TS complexed with dUMP and inhibitor GA9== | | ==E. coli TS complexed with dUMP and inhibitor GA9== |
| - | <StructureSection load='2a9w' size='340' side='right' caption='[[2a9w]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='2a9w' size='340' side='right'caption='[[2a9w]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2a9w]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A9W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2A9W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2a9w]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A9W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A9W FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2BR:2-BROMOPHENOL'>2BR</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=GA9:3,3-BIS(3-BROMO-4-HYDROXYPHENYL)-7-CHLORO-1H,3H-BENZO[DE]ISOCHROMEN-1-ONE'>GA9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.65Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2BR:2-BROMOPHENOL'>2BR</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene>, <scene name='pdbligand=GA9:3,3-BIS(3-BROMO-4-HYDROXYPHENYL)-7-CHLORO-1H,3H-BENZO[DE]ISOCHROMEN-1-ONE'>GA9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">thyA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</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=2a9w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a9w OCA], [https://pdbe.org/2a9w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a9w RCSB], [https://www.ebi.ac.uk/pdbsum/2a9w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a9w ProSAT]</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=2a9w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a9w OCA], [http://pdbe.org/2a9w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2a9w RCSB], [http://www.ebi.ac.uk/pdbsum/2a9w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2a9w ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TYSY_ECOLI TYSY_ECOLI]] Provides the sole de novo source of dTMP for DNA biosynthesis. This protein also binds to its mRNA thus repressing its own translation. | + | [https://www.uniprot.org/uniprot/TYSY_ECOLI TYSY_ECOLI] Provides the sole de novo source of dTMP for DNA biosynthesis. This protein also binds to its mRNA thus repressing its own translation. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Thymidylate synthase|Thymidylate synthase]] | + | *[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Escherichia coli]] |
| - | [[Category: Thymidylate synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Anderson, A C]] | + | [[Category: Anderson AC]] |
| - | [[Category: Costi, M P]] | + | [[Category: Costi MP]] |
| - | [[Category: Ferrari, S]] | + | [[Category: Ferrari S]] |
| - | [[Category: Finer-Moore, J S]] | + | [[Category: Finer-Moore JS]] |
| - | [[Category: Krucinski, J]] | + | [[Category: Krucinski J]] |
| - | [[Category: Neil, R H.O]] | + | [[Category: O'Neil RH]] |
| - | [[Category: Stroud, R M]] | + | [[Category: Stroud RM]] |
| - | [[Category: Protein-inhibitor complex]]
| + | |
| - | [[Category: Transferase]]
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| Structural highlights
2a9w is a 4 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.65Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
TYSY_ECOLI Provides the sole de novo source of dTMP for DNA biosynthesis. This protein also binds to its mRNA thus repressing its own translation.
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 PubMed
The ternary complex crystal structures of Cryptococcus neoformans and Escherichia coli thymidylate synthase (TS) suggest mechanisms of species-specific inhibition of a highly conserved protein. The 2.1 Angstrom structure of C. neoformans TS cocrystallized with substrate and the cofactor analog CB3717 shows that the binding sites for substrate and cofactor are highly conserved with respect to human TS, but that the structure of the cofactor-binding site of C. neoformans TS is less constrained by surrounding residues. This feature might allow C. neoformans TS to form TS-dUMP-inhibitor complexes with a greater range of antifolates than human TS. 3',3-Dibromophenol-4-chloro-1,8-naphthalein (GA9) selectively inhibits both E. coli TS and C. neoformans TS (K(i) = 4 microM) over human TS (K(i) >> 245 microM). The E. coli TS-dUMP-GA9 complex is in an open conformation, similar to that of the apoenzyme crystal structure. The GA9-binding site overlaps the binding site of the pABA-glutamyl moiety of the cofactor. The fact that human apoTS can adopt an unusual fold in which the GA9-binding site is disordered may explain the poor affinity of GA9 for the human enzyme. These observations highlight the critical need to incorporate multiple target conformations in any computational attempt to facilitate drug discovery.
The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.,Finer-Moore JS, Anderson AC, O'Neil RH, Costi MP, Ferrari S, Krucinski J, Stroud RM Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1320-34. Epub 2005, Sep 28. PMID:16204883[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Finer-Moore JS, Anderson AC, O'Neil RH, Costi MP, Ferrari S, Krucinski J, Stroud RM. The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition. Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1320-34. Epub 2005, Sep 28. PMID:16204883 doi:10.1107/S0907444905022638
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