3CSE

Candida glabrata Dihydrofolate Reductase complexed with NADPH and 2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (UCP120B)

Summary for 3CSE

• Entry DOI: 10.2210/pdb3cse/pdb
• Descriptor: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, reductase, oxidoreductase
• Biological source: Candida glabrata (yeast)
• Total number of polymer chains: 2
• Total formula weight: 54970.24

Authors

Liu, J.,Anderson, A.C. (deposition date: 2008-04-09, release date: 2008-11-25, Last modification date: 2024-02-21)

Primary citation

Liu, J.,Bolstad, D.B.,Smith, A.E.,Priestley, N.D.,Wright, D.L.,Anderson, A.C.
Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.
Chem.Biol., 15:990-996, 2008

PubMed Abstract: Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.

PubMed: 18804036
DOI: 10.1016/j.chembiol.2008.07.013

Experimental method

X-RAY DIFFRACTION (1.6 Å)