View source for 6vv9


==Mycobacterium tuberculosis dihydrofolate reductase in complex with JEB300==
<StructureSection load='6vv9' size='340' side='right'caption='[[6vv9]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6vv9]] 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=6VV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VV9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18&#8491;</td></tr>
<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=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=RQ1:5-[4-(1H-indol-3-yl)butoxy]-1-phenyl-1H-pyrazole-4-carboxylic+acid'>RQ1</scene></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=6vv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vv9 OCA], [https://pdbe.org/6vv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vv9 RCSB], [https://www.ebi.ac.uk/pdbsum/6vv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vv9 ProSAT]</span></td></tr>
</table>
== Function ==
[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]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.

Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis.,Ribeiro JA, Hammer A, Libreros-Zuniga GA, Chavez-Pacheco SM, Tyrakis P, de Oliveira GS, Kirkman T, El Bakali J, Rocco SA, Sforca ML, Parise-Filho R, Coyne AG, Blundell TL, Abell C, Dias MVB ACS Infect Dis. 2020 Aug 14;6(8):2192-2201. doi: 10.1021/acsinfecdis.0c00263., Epub 2020 Jul 10. PMID:32603583<ref>PMID:32603583</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6vv9" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis H37Ra]]
[[Category: Chavez-Pacheco SM]]
[[Category: Dias MVB]]
[[Category: Ribeiro JA]]