8A0N

Crystal structure of Candida auris dihydrofolate reductase complexed with NADPH

8A0N の概要

• エントリーDOI: 10.2210/pdb8a0n/pdb
• 分子名称: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: dihydrofolate reductase candida auris nadph, hydrolase
• 由来する生物種: [Candida] auris
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25502.82

構造登録者

Kirkman, T.K.,Dias, M.V.B. (登録日: 2022-05-29, 公開日: 2023-06-14, 最終更新日: 2024-12-25)

主引用文献

Kirkman, T.,Sketcher, A.,de Morais Barroso, V.,Ishida, K.,Tosin, M.,Dias, M.V.B.
Crystal structure of dihydrofolate reductase from the emerging pathogenic fungus Candida auris.
Acta Crystallogr D Struct Biol, 79:735-745, 2023

PubMed Abstract: Candida auris has emerged as a global health problem with a dramatic spread by nosocomial transmission and a high mortality rate. Antifungal therapy for C. auris infections is currently limited due to widespread resistance to fluconazole and amphotericin B and increasing resistance to the front-line drug echinocandin. Therefore, new treatments are urgently required to combat this pathogen. Dihydrofolate reductase (DHFR) has been validated as a potential drug target for Candida species, although no structure of the C. auris enzyme (CauDHFR) has been reported. Here, crystal structures of CauDHFR are reported as an apoenzyme, as a holoenzyme and in two ternary complexes with pyrimethamine and cycloguanil, which are common antifolates, at near-atomic resolution. Preliminary biochemical and biophysical assays and antifungal susceptibility testing with a variety of classical antifolates were also performed, highlighting the enzyme-inhibition rates and the inhibition of yeast growth. These structural and functional data might provide the basis for a novel drug-discovery campaign against this global threat.

PubMed: 37428844
DOI: 10.1107/S2059798323004709

実験手法

X-RAY DIFFRACTION (1.4 Å)