5ISQ
Staphylococcus aureus H30N, F98Y Dihydrofolate Reductase mutant complexed with beta-NADPH and 3'-(3-(2,4-diamino-6-ethylpyrimidin-5-yl)prop-2-yn-1-yl)-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (UCP1106)
Summary for 5ISQ
| Entry DOI | 10.2210/pdb5isq/pdb |
| Related | 5HF0 5HF2 5ISP 5IST |
| Descriptor | Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 4-[3-[3-[2,4-bis(azanyl)-6-ethyl-pyrimidin-5-yl]prop-2-ynyl]-4-methoxy-phenyl]benzoic acid, ... (5 entities in total) |
| Functional Keywords | oxidoreductase, dihydrofolate reductase, nadph, zwitterion, antibiotics |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 1 |
| Total formula weight | 19625.88 |
| Authors | Anderson, A.C.,Reeve, S.M. (deposition date: 2016-03-15, release date: 2017-06-28, Last modification date: 2024-04-03) |
| Primary citation | Reeve, S.M.,Scocchera, E.,Ferreira, J.J.,G-Dayanandan, N.,Keshipeddy, S.,Wright, D.L.,Anderson, A.C. Charged Propargyl-Linked Antifolates Reveal Mechanisms of Antifolate Resistance and Inhibit Trimethoprim-Resistant MRSA Strains Possessing Clinically Relevant Mutations. J. Med. Chem., 59:6493-6500, 2016 Cited by PubMed Abstract: Drug-resistant enzymes must balance catalytic function with inhibitor destabilization to provide a fitness advantage. This sensitive balance, often involving very subtle structural changes, must be achieved through a selection process involving a minimal number of eligible point mutations. As part of a program to design propargyl-linked antifolates (PLAs) against trimethoprim-resistant dihydrofolate reductase (DHFR) from Staphylococcus aureus, we have conducted a thorough study of several clinically observed chromosomal mutations in the enzyme at the cellular, biochemical, and structural levels. Through this work, we have identified a promising lead series that displays significantly greater activity against these mutant enzymes and strains than TMP. The best inhibitors have enzyme inhibition and MIC values near or below that of trimethoprim against wild-type S. aureus. Moreover, these studies employ a series of crystal structures of several mutant enzymes bound to the same inhibitor; analysis of the structures reveals a more detailed molecular understanding of drug resistance in this important enzyme. PubMed: 27308944DOI: 10.1021/acs.jmedchem.6b00688 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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