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5ecx

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==Klebsiella pneumoniae DfrA1 complexed with NADPH and 6-ethyl-5-(3-(6-(pyridin-4-yl)benzo[d][1,3]dioxol-4-yl)but-1-yn-1-yl)pyrimidine-2,4-diamine==
==Klebsiella pneumoniae DfrA1 complexed with NADPH and 6-ethyl-5-(3-(6-(pyridin-4-yl)benzo[d][1,3]dioxol-4-yl)but-1-yn-1-yl)pyrimidine-2,4-diamine==
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<StructureSection load='5ecx' size='340' side='right' caption='[[5ecx]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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<StructureSection load='5ecx' size='340' side='right'caption='[[5ecx]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ecx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ECX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ECX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ecx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ECX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ECX 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=5N1:6-ETHYL-5-[(3~{S})-3-(6-PYRIDIN-4-YL-1,3-BENZODIOXOL-4-YL)BUT-1-YNYL]PYRIMIDINE-2,4-DIAMINE'>5N1</scene>, <scene name='pdbligand=GLV:GLYOXYLIC+ACID'>GLV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 1.95&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ecc|5ecc]]</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=5N1:6-ETHYL-5-[(3~{S})-3-(6-PYRIDIN-4-YL-1,3-BENZODIOXOL-4-YL)BUT-1-YNYL]PYRIMIDINE-2,4-DIAMINE'>5N1</scene>, <scene name='pdbligand=GLV:GLYOXYLIC+ACID'>GLV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dfrA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</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=5ecx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ecx OCA], [https://pdbe.org/5ecx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ecx RCSB], [https://www.ebi.ac.uk/pdbsum/5ecx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ecx 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=5ecx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ecx OCA], [http://pdbe.org/5ecx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ecx RCSB], [http://www.ebi.ac.uk/pdbsum/5ecx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ecx ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/A4GRC7_KLEPN A4GRC7_KLEPN]
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Multidrug-resistant Enterobacteriaceae, notably Escherichia coli and Klebsiella pneumoniae, have become major health concerns worldwide. Resistance to effective therapeutics is often carried by class I and II integrons that can confer insensitivity to carbapenems, extended spectrum beta-lactamases, the antifolate trimethoprim, fluoroquinolones, and aminoglycosides. Specifically of interest to the study here, a prevalent gene (dfrA1) coding for an insensitive dihydrofolate reductase (DHFR) confers 190- or 1000-fold resistance to trimethoprim for K. pneumoniae and E. coli, respectively. Attaining inhibition of both the wild-type and resistant forms of the enzyme is critical for new antifolates. For several years, we have been developing the propargyl-linked antifolates (PLAs) as effective inhibitors against trimethoprim-resistant DHFR enzymes. Here, we show that the PLAs are active against both the wild-type and DfrA1 DHFR proteins. We report two high-resolution crystal structures of DfrA1 bound to potent PLAs. The structure-activity relationships and crystal structures will be critical in driving the design of broadly active inhibitors against wild-type and resistant DHFR.
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Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates.,Lombardo MN, G-Dayanandan N, Wright DL, Anderson AC ACS Infect Dis. 2016 Feb 12;2(2):149-56. doi: 10.1021/acsinfecdis.5b00129. Epub, 2016 Jan 4. PMID:27624966<ref>PMID:27624966</ref>
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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 5ecx" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Dihydrofolate reductase|Dihydrofolate reductase]]
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Anderson, A C]]
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[[Category: Klebsiella pneumoniae]]
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[[Category: Lombardo, M N]]
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[[Category: Large Structures]]
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[[Category: Antifolate]]
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[[Category: Anderson AC]]
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[[Category: Dfra1]]
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[[Category: Lombardo MN]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Plasmid borne resistance]]
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Current revision

Klebsiella pneumoniae DfrA1 complexed with NADPH and 6-ethyl-5-(3-(6-(pyridin-4-yl)benzo[d][1,3]dioxol-4-yl)but-1-yn-1-yl)pyrimidine-2,4-diamine

PDB ID 5ecx

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