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==X-ray structure of Escherichia coli dihydrofolate reductase in complex with trimethoprim== | ==X-ray structure of Escherichia coli dihydrofolate reductase in complex with trimethoprim== | ||
<StructureSection load='6xg5' size='340' side='right'caption='[[6xg5]]' scene=''> | <StructureSection load='6xg5' size='340' side='right'caption='[[6xg5]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XG5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XG5 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6xg5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XG5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XG5 FirstGlance]. <br> | ||
</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=6xg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xg5 OCA], [https://pdbe.org/6xg5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xg5 RCSB], [https://www.ebi.ac.uk/pdbsum/6xg5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xg5 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=TOP:TRIMETHOPRIM'>TOP</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1drh|1drh]], [[7dfr|7dfr]], [[1dre|1dre]], [[1rh3|1rh3]], [[6xg4|6xg4]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folA, tmrA, b0048, JW0047 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6xg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xg5 OCA], [https://pdbe.org/6xg5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xg5 RCSB], [https://www.ebi.ac.uk/pdbsum/6xg5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xg5 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/DYR_ECOLI DYR_ECOLI]] 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;"> | |||
== Publication Abstract from PubMed == | |||
The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4'-desmethyltrimethoprim (4'-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4'-DTMP than in the presence of TMP. We find that 4'-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance. | |||
A trimethoprim derivative impedes antibiotic resistance evolution.,Manna MS, Tamer YT, Gaszek I, Poulides N, Ahmed A, Wang X, Toprak FCR, Woodard DR, Koh AY, Williams NS, Borek D, Atilgan AR, Hulleman JD, Atilgan C, Tambar U, Toprak E Nat Commun. 2021 May 19;12(1):2949. doi: 10.1038/s41467-021-23191-z. PMID:34011959<ref>PMID:34011959</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6xg5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Dihydrofolate reductase]] | |||
[[Category: Ecoli]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Borek D]] | [[Category: Borek, D]] | ||
[[Category: Gaszek | [[Category: Gaszek, I K]] | ||
[[Category: Manna | [[Category: Manna, M S]] | ||
[[Category: Toprak E]] | [[Category: Toprak, E]] | ||
[[Category: Complex]] | |||
[[Category: Dhfr]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Trimethoprim]] | |||