6V3M

Crystal structure of 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF) Burkholderia pseudomallei in compomplex with ligand HGN-0961 (BSI110840)

Summary for 6V3M

• Entry DOI: 10.2210/pdb6v3m/pdb
• Descriptor: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, ZINC ION, 5-{[(propan-2-yl)carbamoyl]amino}-1,3,4-thiadiazole-2-sulfonamide, ... (7 entities in total)
• Functional Keywords: ssgcid, structural genomics, seattle structural genomics center for infectious disease, burkholderia pseudomallei, 2-c-methyl-d-erythritol 2, 4-cyclodiphosphate synthase, hgn-0961, lyase
• Biological source: Burkholderia pseudomallei (strain 1710b)
• Total number of polymer chains: 3
• Total formula weight: 60164.45

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2019-11-26, release date: 2020-12-09, Last modification date: 2025-04-09)

Primary citation

Grote, D.,Stewart, C.G.,Daraji, D.G.,Enayati, P.,Braverman, K.N.,Romanaggi, C.,Bolejack, M.J.,Yano, J.K.,Abendroth, J.,Dranow, D.M.,Pierce, P.G.,Lorimer, D.D.,Horanyi, P.S.,Staker, B.L.,Edwards, T.E.,Myler, P.J.,Horn, J.R.,Hagen, T.J.
Analysis of Burkholderia pseudomallei IspF in complex with sulfapyridine, sulfamonomethoxine, ethoxzolamide and acetazolamide.
Acta Crystallogr.,Sect.F, 81:138-145, 2025

PubMed Abstract: The methylerythritol phosphate (MEP) pathway is a metabolic pathway that produces the isoprenoids isopentyl pyrophosphate and dimethylallyl pyrophosphate. Notably, the MEP pathway is present in bacteria and not in mammals, which makes the enzymes of the MEP pathway attractive targets for the discovery of new anti-infective agents due to the reduced chances of off-target interactions leading to side effects. There are seven enzymes in the MEP pathway, the fifth of which is IspF. Crystal structures of Burkholderia pseudomallei IspF were determined with five different sulfonamide ligands bound. The sulfonamide-containing ligands were ethoxzolamide, acetazolamide, sulfapyridine and sulfamonomethoxine. The fifth bound ligand was a synthetic analog of acetazolamide. All ligands coordinated to the active-site Zn ion through the sulfonamide group, although sulfapyridine and sulfamonomethoxine, both of which are known antibacterial agents, possess similar binding interactions that are distinct from the other three sulfonamides. These structural data will aid in the discovery of new IspF inhibitors.

PubMed: 40035494
DOI: 10.1107/S2053230X25001414

Experimental method

X-RAY DIFFRACTION (1.55 Å)