6nne

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<StructureSection load='6nne' size='340' side='right'caption='[[6nne]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
<StructureSection load='6nne' size='340' side='right'caption='[[6nne]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6nne]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycta Mycta]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NNE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NNE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6nne]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Ra Mycobacterium tuberculosis H37Ra]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NNE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NNE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=KUP:5-[(3,4-dimethoxyphenyl)methyl]pyrimidine-2,4-diamine'>KUP</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.595&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dfrA, MRA_2788 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=419947 MYCTA])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=KUP:5-[(3,4-dimethoxyphenyl)methyl]pyrimidine-2,4-diamine'>KUP</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6nne FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nne OCA], [https://pdbe.org/6nne PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nne RCSB], [https://www.ebi.ac.uk/pdbsum/6nne PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nne ProSAT]</span></td></tr>
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<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=6nne FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nne OCA], [http://pdbe.org/6nne PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nne RCSB], [http://www.ebi.ac.uk/pdbsum/6nne PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nne ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/A5U6B6_MYCTA A5U6B6_MYCTA]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.[PIRNR:PIRNR000194]
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[https://www.uniprot.org/uniprot/A5U6B6_MYCTA A5U6B6_MYCTA] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.[PIRNR:PIRNR000194]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tuberculosis is a disease caused by Mycobacterium tuberculosis and is the leading cause of death from a single infectious pathogen, with a high prevalence in developing countries in Africa and Asia. There still is a need for the development or repurposing of novel therapies to combat this disease owing to the long-term nature of current therapies and because of the number of reported resistant strains. Here, structures of dihydrofolate reductase from M. tuberculosis (MtDHFR), which is a key target of the folate pathway, are reported in complex with four antifolates, pyrimethamine, cycloguanil, diaverdine and pemetrexed, and its substrate dihydrofolate in order to understand their binding modes. The structures of all of these complexes were obtained in the closed-conformation state of the enzyme and a fine structural analysis indicated motion in key regions of the substrate-binding site and different binding modes of the ligands. In addition, the affinities, through Kd measurement, of diaverdine and methotrexate have been determined; MtDHFR has a lower affinity (highest Kd) for diaverdine than pyrimethamine and trimethoprim, and a very high affinity for methotrexate, as expected. The structural comparisons and analysis described in this work provide new information about the plasticity of MtDHFR and the binding effects of different antifolates.
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Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates.,Ribeiro JA, Chavez-Pacheco SM, de Oliveira GS, Silva CDS, Giudice JHP, Libreros-Zuniga GA, Dias MVB Acta Crystallogr D Struct Biol. 2019 Jul 1;75(Pt 7):682-693. doi:, 10.1107/S205979831900901X. Epub 2019 Jul 4. PMID:31282477<ref>PMID:31282477</ref>
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==See Also==
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6nne" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Dihydrofolate reductase]]
 
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Mycta]]
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[[Category: Mycobacterium tuberculosis H37Ra]]
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[[Category: Chavez-Pacheco, S M]]
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[[Category: Chavez-Pacheco SM]]
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[[Category: Dias, M V.B]]
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[[Category: Dias MVB]]
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[[Category: Ribeiro, J A]]
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[[Category: Ribeiro JA]]
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[[Category: Antifolate]]
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[[Category: Oxidoreductase]]
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Current revision

Crystal structure of Dihydrofolate reductase from Mycobacterium tuberculosis in complex with diaverdine

PDB ID 6nne

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