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| | ==Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in an open conformation.== | | ==Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in an open conformation.== |
| - | <StructureSection load='4klx' size='340' side='right' caption='[[4klx]], [[Resolution|resolution]] 1.23Å' scene=''> | + | <StructureSection load='4klx' size='340' side='right'caption='[[4klx]], [[Resolution|resolution]] 1.23Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4klx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KLX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KLX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4klx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KLX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KLX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATR:2-MONOPHOSPHOADENOSINE-5-DIPHOSPHATE'>ATR</scene>, <scene name='pdbligand=ETE:2-{2-[2-2-(METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>ETE</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATR:2-MONOPHOSPHOADENOSINE-5-DIPHOSPHATE'>ATR</scene>, <scene name='pdbligand=ETE:2-{2-[2-2-(METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>ETE</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4kl9|4kl9]], [[4km0|4km0]], [[4km2|4km2]], [[4kne|4kne]]</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=4klx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4klx OCA], [https://pdbe.org/4klx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4klx RCSB], [https://www.ebi.ac.uk/pdbsum/4klx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4klx ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dfrA, folA, H37Rv, MT2833, MTV002.28c, Rv2763c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=4klx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4klx OCA], [http://pdbe.org/4klx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4klx RCSB], [http://www.ebi.ac.uk/pdbsum/4klx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4klx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DYR_MYCTU DYR_MYCTU]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. | + | [https://www.uniprot.org/uniprot/DYR_MYCTU DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4klx" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4klx" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dihydrofolate reductase]] | + | [[Category: Large Structures]] |
| - | [[Category: Blundell, T L]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Dias, M V.B]] | + | [[Category: Blundell TL]] |
| - | [[Category: Tyrakis, P]] | + | [[Category: Dias MVB]] |
| - | [[Category: Oxidoreductase]] | + | [[Category: Tyrakis P]] |
| - | [[Category: Reductase]]
| + | |
| Structural highlights
Function
DYR_MYCTU Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Publication Abstract from PubMed
Inhibition of the biosynthesis of tetrahydrofolate (THF) has long been a focus in the treatment of both cancer and infectious diseases. Dihydrofolate reductase (DHFR), which catalyzes the last step, is one of the most thoroughly explored targets of this pathway, but there are no DHFR inhibitors used for tuberculosis treatment. Here, we report a structural, site-directed mutagenesis and calorimetric analysis of Mycobacterium tuberculosis DHFR (MtDHFR) in complex with classical DHFR inhibitors. Our study provides insights into the weak inhibition of MtDHFR by trimethoprim and other antifolate drugs, such as pyrimethamine and cycloguanil. The construction of the mutant Y100F, together with calorimetric studies, gives insights into low affinity of MtDHFR for classical DHFR inhibitors. Finally, the structures of MtDHFR in complex with pyrimethamine and cycloguanil define important interactions in the active site and provide clues to the more effective design of antibiotics targeted against MtDHFR.
Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs.,Dias MV, Tyrakis P, Domingues RR, Leme AF, Blundell TL Structure. 2013 Nov 6. pii: S0969-2126(13)00395-X. doi:, 10.1016/j.str.2013.09.022. PMID:24210757[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dias MV, Tyrakis P, Domingues RR, Leme AF, Blundell TL. Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs. Structure. 2013 Nov 6. pii: S0969-2126(13)00395-X. doi:, 10.1016/j.str.2013.09.022. PMID:24210757 doi:http://dx.doi.org/10.1016/j.str.2013.09.022
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