4fgh

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==S. aureus dihydrofolate reductase co-crystallized with ethyl-DAP isobutenyl-dihydrophthalazine inhibitor==
==S. aureus dihydrofolate reductase co-crystallized with ethyl-DAP isobutenyl-dihydrophthalazine inhibitor==
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<StructureSection load='4fgh' size='340' side='right' caption='[[4fgh]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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<StructureSection load='4fgh' size='340' side='right'caption='[[4fgh]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4fgh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FGH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FGH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4fgh]] 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=4FGH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FGH 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=0U6:(2E)-3-{5-[(2,4-DIAMINO-6-ETHYLPYRIMIDIN-5-YL)METHYL]-2,3-DIMETHOXYPHENYL}-1-[(1S)-1-(2-METHYLPROP-1-EN-1-YL)PHTHALAZIN-2(1H)-YL]PROP-2-EN-1-ONE'>0U6</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]] 2.5&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3m08|3m08]], [[4fgg|4fgg]]</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=0U6:(2E)-3-{5-[(2,4-DIAMINO-6-ETHYLPYRIMIDIN-5-YL)METHYL]-2,3-DIMETHOXYPHENYL}-1-[(1S)-1-(2-METHYLPROP-1-EN-1-YL)PHTHALAZIN-2(1H)-YL]PROP-2-EN-1-ONE'>0U6</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">DHFR, folA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</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=4fgh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fgh OCA], [https://pdbe.org/4fgh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fgh RCSB], [https://www.ebi.ac.uk/pdbsum/4fgh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fgh ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=4fgh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fgh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fgh RCSB], [http://www.ebi.ac.uk/pdbsum/4fgh PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://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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[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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(+/-)-6-Alkyl-2,4-diaminopyrimidine-based inhibitors of bacterial dihydrofolate reductase (DHFR) have been prepared and evaluated for biological potency against Bacillus anthracis and Staphylococcus aureus. Biological studies revealed attenuated activity relative to earlier structures lacking substitution at C6 of the diaminopyrimidine moiety, though minimum inhibitory concentration (MIC) values are in the 0.125-8 mug mL(-1) range for both organisms. This effect was rationalized from three- dimensional X-ray structure studies that indicate the presence of a side pocket containing two water molecules adjacent to the main binding pocket. Because of the hydrophobic nature of the substitutions at C6, the main interactions are with protein residues Leu 20 and Leu 28. These interactions lead to a minor conformational change in the protein, which opens the pocket containing these water molecules such that it becomes continuous with the main binding pocket. These water molecules are reported to play a critical role in the catalytic reaction, highlighting a new area for inhibitor expansion within the limited architectural variation at the catalytic site of bacterial DHFR.
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Inhibition of Bacterial Dihydrofolate Reductase by 6-Alkyl-2,4-diaminopyrimidines.,Nammalwar B, Bourne CR, Bunce RA, Wakeham N, Bourne PC, Ramnarayan K, Mylvaganam S, Berlin KD, Barrow EW, Barrow WW ChemMedChem. 2012 Aug 28. doi: 10.1002/cmdc.201200291. PMID:22930550<ref>PMID:22930550</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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==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: Dihydrofolate reductase]]
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[[Category: Large Structures]]
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[[Category: Barrow, W W]]
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[[Category: Staphylococcus aureus]]
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[[Category: Bourne, C R]]
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[[Category: Barrow WW]]
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[[Category: Oxidoreductase-inhibitor complex]]
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[[Category: Bourne CR]]

Current revision

S. aureus dihydrofolate reductase co-crystallized with ethyl-DAP isobutenyl-dihydrophthalazine inhibitor

PDB ID 4fgh

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