7T1G

Crystal structure of CAB1 Pantothenate Kinase from Saccharomyces cerevisiae in complex with compound YU385595

Summary for 7T1G

• Entry DOI: 10.2210/pdb7t1g/pdb
• Related: 6UJ5 7T1H 7T1I
• Descriptor: Pantothenate kinase CAB1, (8S)-N~2~-[(4-tert-butylphenyl)methyl]-N~7~,N~7~-dimethyl-5-[(morpholin-4-yl)methyl][1,2,4]triazolo[1,5-a]pyrimidine-2,7-diamine (3 entities in total)
• Functional Keywords: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Saccharomyces cerevisiae S288C
• Total number of polymer chains: 2
• Total formula weight: 84371.93

Authors

Gihaz, S.,Ben Mamoun, C. (deposition date: 2021-12-01, release date: 2022-10-05, Last modification date: 2023-10-18)

Primary citation

Gihaz, S.,Gareiss, P.,Choi, J.Y.,Renard, I.,Pal, A.C.,Surovsteva, Y.,Chiu, J.E.,Thekkiniath, J.,Plummer, M.,Hungerford, W.,Montgomery, M.L.,Hosford, A.,Adams, E.M.,Lightfoot, J.D.,Fox 3rd, D.,Ojo, K.K.,Staker, B.L.,Fuller, K.,Ben Mamoun, C.
High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development.
Structure, 30:1494-, 2022

PubMed Abstract: Fungal infections are the leading cause of mortality by eukaryotic pathogens, with an estimated 150 million severe life-threatening cases and 1.7 million deaths reported annually. The rapid emergence of multidrug-resistant fungal isolates highlights the urgent need for new drugs with new mechanisms of action. In fungi, pantothenate phosphorylation, catalyzed by PanK enzyme, is the first step in the utilization of pantothenic acid and coenzyme A biosynthesis. In all fungi sequenced so far, this enzyme is encoded by a single PanK gene. Here, we report the crystal structure of a fungal PanK alone as well as with high-affinity inhibitors from a single chemotype identified through a high-throughput chemical screen. Structural, biochemical, and functional analyses revealed mechanisms governing substrate and ligand binding, dimerization, and catalysis and helped identify new compounds that inhibit the growth of several Candida species. The data validate PanK as a promising target for antifungal drug development.

PubMed: 36167065
DOI: 10.1016/j.str.2022.09.001

Experimental method

X-RAY DIFFRACTION (2 Å)