View source for 6pbo


==Staphylococcus aureus Dihydrofolate reductase in complex with NADPH and UCP1232==
<StructureSection load='6pbo' size='340' side='right'caption='[[6pbo]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6pbo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PBO 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]] 1.649&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=O71:(4-{6-[(2S)-4-(2,4-diamino-6-ethylpyrimidin-5-yl)but-3-yn-2-yl]-2H-1,3-benzodioxol-4-yl}phenyl)acetic+acid'>O71</scene>, <scene name='pdbligand=XNP:TRICYCLIC+NADPH'>XNP</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=6pbo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pbo OCA], [https://pdbe.org/6pbo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pbo RCSB], [https://www.ebi.ac.uk/pdbsum/6pbo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pbo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
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== Publication Abstract from PubMed ==
The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms. Using a structure-based approach, we have developed a novel class of ionized nonclassical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural, and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMP resistant (TMP(R)) and methicillin resistant Staphylococcus aureus (MRSA) isolates.

Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus.,Reeve SM, Si D, Krucinska J, Yan Y, Viswanathan K, Wang S, Holt GT, Frenkel MS, Ojewole AA, Estrada A, Agabiti SS, Alverson JB, Gibson ND, Priestley ND, Wiemer AJ, Donald BR, Wright DL ACS Infect Dis. 2019 Oct 15. doi: 10.1021/acsinfecdis.9b00222. PMID:31565920<ref>PMID:31565920</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6pbo" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Reeve SM]]
[[Category: Wright DL]]