8CRH

Crystal structure of Candida auris dihydrofolate reductase complexed with NADPH and cycloguanil

Summary for 8CRH

• Entry DOI: 10.2210/pdb8crh/pdb
• Descriptor: Dihydrofolate reductase, 5-(4-chlorophenyl)-6,6-dimethyl-1,4-dihydro-1,3,5-triazine-2,4-diamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: dihydrofolate reductase candida auris nadph cycloguanil, hydrolase
• Biological source: [Candida] auris
• Total number of polymer chains: 2
• Total formula weight: 51081.30

Authors

Kirkman, T.J.,Dias, M.V.B. (deposition date: 2023-03-08, release date: 2023-08-02, Last modification date: 2024-06-19)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.3 Å)