3NJ8

Crystal structure of T. gondii enoyl acyl carrier protein reductase with bound triclosan like inhibitor

Summary for 3NJ8

• Entry DOI: 10.2210/pdb3nj8/pdb
• Related: 2O2S 2O2Y 2O50
• Descriptor: Enoyl-acyl carrier reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-chloro-4-(2-hydroxy-4-propylphenoxy)benzonitrile, ... (4 entities in total)
• Functional Keywords: enoyl reductase, enr triclosan, rossmann nad binding fold, nadh binding, oxidoreductase
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 2
• Total formula weight: 68685.44

Authors

Muench, S.P.,Ruzheinikov, S.N.,Rice, D.W. (deposition date: 2010-06-17, release date: 2010-09-29, Last modification date: 2024-02-21)

Primary citation

Tipparaju, S.K.,Muench, S.P.,Mui, E.J.,Ruzheinikov, S.N.,Lu, J.Z.,Hutson, S.L.,Kirisits, M.J.,Prigge, S.T.,Roberts, C.W.,Henriquez, F.L.,Kozikowski, A.P.,Rice, D.W.,McLeod, R.L.
Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase.
J.Med.Chem., 53:6287-6300, 2010

PubMed Abstract: Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s < or = 6 microM without toxicity to host cells, three compounds have IC(90)s < 45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.

PubMed: 20698542
DOI: 10.1021/jm9017724

Experimental method

X-RAY DIFFRACTION (2.7 Å)