3I8A
Staphylococcus aureus H30N, F98Y Dihydrofolate Reductase complexed with NADPH and 2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (UCP120B)
Summary for 3I8A
| Entry DOI | 10.2210/pdb3i8a/pdb |
| Related | 3FQ0 3FQO |
| Descriptor | Dihydrofolate reductase, 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total) |
| Functional Keywords | nadph, one-carbon metabolism, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 1 |
| Total formula weight | 19065.30 |
| Authors | Frey, K.M.,Lombardo, M.N.,Anderson, A.C. (deposition date: 2009-07-09, release date: 2010-02-09, Last modification date: 2023-09-06) |
| Primary citation | Frey, K.M.,Lombardo, M.N.,Wright, D.L.,Anderson, A.C. Towards the understanding of resistance mechanisms in clinically isolated trimethoprim-resistant, methicillin-resistant Staphylococcus aureus dihydrofolate reductase. J.Struct.Biol., 170:93-97, 2010 Cited by PubMed Abstract: Resistance to therapeutics such as trimethoprim-sulfamethoxazole has become an increasing problem in strains of methicillin-resistant Staphylococcus aureus (MRSA). Clinically isolated trimethoprim-resistant strains reveal a double mutation, H30N/F98Y, in dihydrofolate reductase (DHFR). In order to develop novel and effective therapeutics against these resistant strains, we evaluated a series of propargyl-linked antifolate lead compounds for inhibition of the mutant enzyme. For the propargyl-linked antifolates, the F98Y mutation generates minimal (between 1.2- and 6-fold) losses of affinity and the H30N mutation generates greater losses (between 2.4- and 48-fold). Conversely, trimethoprim affinity is largely diminished by the F98Y mutation (36-fold) and is not affected by the H30N mutation. In order to elucidate a mechanism of resistance, we determined a crystal structure of a complex of this double mutant with a lead propargyl-linked antifolate. This structure suggests a resistance mechanism consistent both for the propargyl-linked class of antifolates and for trimethoprim that is based on the loss of a conserved water-mediated hydrogen bond. PubMed: 20026215DOI: 10.1016/j.jsb.2009.12.011 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.41 Å) |
Structure validation
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