7R6G

Crystal structure of DfrA5 dihydrofolate reductase in complex with TRIMETHOPRIM and NADPH

7R6G の概要

• エントリーDOI: 10.2210/pdb7r6g/pdb
• 分子名称: Dihydrofolate reductase type 5, TRIMETHOPRIM, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: dihydrofolate reductase, oxidoreductase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37261.55

構造登録者

Estrada, A.,Wright, D.,Krucinska, J.,Erlandsen, H. (登録日: 2021-06-22, 公開日: 2022-06-29, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.61 Å)