8V5G

Crystal Structure of Acetyl-CoA synthetase from Cryptococcus neoformans H99 in complex with an ethylsulfamide AMP inhibitor

Summary for 8V5G

• Entry DOI: 10.2210/pdb8v5g/pdb
• Descriptor: Acetyl-coenzyme A synthetase, 5'-deoxy-5'-(ethylsulfamamido)adenosine, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: ssgcid, structural genomics, seattle structural genomics center for infectious disease, acetyl-coenzyme a synthetase 2, ligase
• Biological source: Cryptococcus neoformans var. grubii
• Total number of polymer chains: 3
• Total formula weight: 233209.48

Authors

Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2023-11-30, release date: 2023-12-13, Last modification date: 2025-09-17)

Primary citation

Daraji, D.G.,Jezewski, A.J.,Alden, K.M.,Propp, J.P.,Heene, M.E.,Soldan, C.A.,Liu, L.,Battaile, K.P.,Lovell, S.,Staker, B.L.,Krysan, D.J.,Hagen, T.J.
Synthesis and evaluation of acyl-AMP phosphate isosteres as inhibitors of fungal acetyl CoA synthetase.
Bioorg.Med.Chem.Lett., 129:130389-130389, 2025

PubMed Abstract: Acetyl-CoA synthetase (ACS) is a member of the adenylate-forming enzymes superfamily. This enzyme plays a crucial role in cellular metabolism. While ACS enzymes are non-essential in mammals, they are essential in some fungal species and parasites that are pathogenic to humans. Hence, inhibition of the ACS enzyme is an emerging target for the development of novel anti-infectives. Alkyl AMP esters and acyl sulfamoyl adenosine (Acyl-AMS) are potent inhibitors of fungal ACS enzymes by mimicingthe acyl-AMP enzyme intermediate. Molecular docking studies were performed to facilitate the design of analogs and to explore their potential ligand-binding interactions with the ACS enzyme. A series of acyl-AMP isosteres were synthesized and screened for inhibitory activity against fungal ACS enzymes. Notably, Compound 14 was successfully crystallized with the Cryptococcus neoformans ACS1 enzyme, providing valuable structural insight for future inhibitor design.

PubMed: 40885291
DOI: 10.1016/j.bmcl.2025.130389

Experimental method

X-RAY DIFFRACTION (2.5 Å)