View source for 6prb


==S. aureus dihydrofolate reductase co-crystallized with cyclopropyl-dimethyoxydihydropthalazine inhibitor and NADP(H)==
<StructureSection load='6prb' size='340' side='right'caption='[[6prb]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6prb]] 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=6PRB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PRB 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=OWM:(2E)-1-[(1R)-1-cyclopropyl-6,7-dimethoxyphthalazin-2(1H)-yl]-3-{5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}prop-2-en-1-one'>OWM</scene>, <scene name='pdbligand=R0Y:(2E)-1-[(1S)-1-cyclopropyl-6,7-dimethoxy-3,4-dihydrophthalazin-2(1H)-yl]-3-{5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}prop-2-en-1-one'>R0Y</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=6prb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6prb OCA], [https://pdbe.org/6prb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6prb RCSB], [https://www.ebi.ac.uk/pdbsum/6prb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6prb 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Staphylococcus aureus (Sa) is a serious concern due to increasing resistance to antibiotics. The bacterial dihydrofolate reductase enzyme is effectively inhibited by trimethoprim, a compound with antibacterial activity. Previously, we reported a trimethoprim derivative containing an acryloyl linker and a dihydophthalazine moiety demonstrating increased potency against S. aureus. We have expanded this series and assessed in vitro enzyme inhibition (Ki) and whole cell growth inhibition properties (MIC). Modifications were focused at a chiral carbon within the phthalazine heterocycle, as well as simultaneous modification at positions on the dihydrophthalazine. MIC values increased from 0.0626-0.5 mug/mL into the 0.5-1 mug/mL range when the edge positions were modified with either methyl or methoxy groups. Changes at the chiral carbon affected Ki measurements but with little impact on MIC values. Our structural data revealed accommodation of predominantly the S-enantiomer of the inhibitors within the folate-binding pocket. Longer modifications at the chiral carbon, such as p-methylbenzyl, protrude from the pocket into solvent and result in poorer Ki values, as do modifications with greater torsional freedom, such as 1-ethylpropyl. The most efficacious Ki was 0.7 +/- 0.3 nM, obtained with a cyclopropyl derivative containing dimethoxy modifications at the dihydrophthalazine edge. The co-crystal structure revealed an alternative placement of the phthalazine moiety into a shallow surface at the edge of the site that can accommodate either enantiomer of the inhibitor. The current design, therefore, highlights how to engineer specific placement of the inhibitor within this alternative pocket, which in turn maximizes the enzyme inhibitory properties of racemic mixtures.

Inhibitor design to target a unique feature in the folate pocket of Staphylococcus aureus dihydrofolate reductase.,Muddala NP, White JC, Nammalwar B, Pratt I, Thomas LM, Bunce RA, Berlin KD, Bourne CR Eur J Med Chem. 2020 May 20;200:112412. doi: 10.1016/j.ejmech.2020.112412. PMID:32502861<ref>PMID:32502861</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6prb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Bourne CR]]
[[Category: Thomas LM]]