7MYM

Crystal structure of Escherichia coli dihydrofolate reductase in complex with TRIMETHOPRIM and NADPH

Summary for 7MYM

• Entry DOI: 10.2210/pdb7mym/pdb
• Descriptor: Dihydrofolate reductase, ARGININE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: dihydrofolate reductase, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 3
• Total formula weight: 57893.86

Authors

Erlandsen, H.,Wright, D.,Krucinska, J. (deposition date: 2021-05-21, release date: 2022-06-01, Last modification date: 2023-10-18)

Primary citation

Krucinska, J.,Lombardo, M.N.,Erlandsen, H.,Estrada, A.,Si, D.,Viswanathan, K.,Wright, D.L.
Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens.
Commun Biol, 5:459-459, 2022

PubMed Abstract: Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development against antibiotic resistant pathogens. Preliminary screening of novel antifolates revealed related chemotypes that showed high levels of inhibitory potency against Escherichia coli chromosomal DHFR (EcDHFR), DfrA1, and DfrA5. Kinetics and biophysical analysis, coupled with crystal structures of trimethoprim bound to EcDHFR, DfrA1 and DfrA5, and two propargyl-linked antifolates (PLA) complexed with EcDHFR, DfrA1 and DfrA5, were determined to define structural features of the substrate binding pocket and guide synthesis of pan-DHFR inhibitors.

PubMed: 35562546
DOI: 10.1038/s42003-022-03384-y

Experimental method

X-RAY DIFFRACTION (3.04 Å)