4lek
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4lek]] 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=4LEK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LEK FirstGlance]. <br> | <table><tr><td colspan='2'>[[4lek]] 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=4LEK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LEK FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1DN:7-[5,6-DIMETHOXY-2-(1,3-THIAZOL-2-YL)-1H-BENZIMIDAZOL-1-YL]QUINAZOLINE-2,4-DIAMINE'>1DN</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1DN:7-[5,6-DIMETHOXY-2-(1,3-THIAZOL-2-YL)-1H-BENZIMIDAZOL-1-YL]QUINAZOLINE-2,4-DIAMINE'>1DN</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=4lek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lek OCA], [https://pdbe.org/4lek PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lek RCSB], [https://www.ebi.ac.uk/pdbsum/4lek PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lek ProSAT]</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=4lek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lek OCA], [https://pdbe.org/4lek PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lek RCSB], [https://www.ebi.ac.uk/pdbsum/4lek PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lek ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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. | [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 == | ||
| - | A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 mug/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 mug/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series. | ||
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| - | Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines.,Lam T, Hilgers MT, Cunningham ML, Kwan BP, Nelson KJ, Brown-Driver V, Ong V, Trzoss M, Hough G, Shaw KJ, Finn J J Med Chem. 2014 Feb 13;57(3):651-68. doi: 10.1021/jm401204g. Epub 2014 Jan 16. PMID:24428639<ref>PMID:24428639</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4lek" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines
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