4NOG

Crystal structure of a putative ornithine aminotransferase from Toxoplasma gondii ME49 in complex with pyrodoxal-5'-phosphate

4NOG の概要

• エントリーDOI: 10.2210/pdb4nog/pdb
• 分子名称: Putative ornithine aminotransferase, mitochondrial, PYRIDOXAL-5'-PHOSPHATE, BETA-MERCAPTOETHANOL, ... (7 entities in total)
• 機能のキーワード: structural genomics, niaid, national institute of allergy and infectious diseases, center for structural genomics of infectious diseases, csgid, ornithine aminotransferase, toxoplasma, transferase
• 由来する生物種: Toxoplasma gondii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99080.83

構造登録者

Filippova, E.V.,Halavaty, A.,Ruan, J.,Shuvalova, L.,Flores, K.,Dubrovska, I.,Ngo, H.,Shanmugam, D.,Roos, D.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2013-11-19, 公開日: 2013-12-04, 最終更新日: 2023-09-20)

主引用文献

Lykins, J.D.,Filippova, E.V.,Halavaty, A.S.,Minasov, G.,Zhou, Y.,Dubrovska, I.,Flores, K.J.,Shuvalova, L.A.,Ruan, J.,El Bissati, K.,Dovgin, S.,Roberts, C.W.,Woods, S.,Moulton, J.D.,Moulton, H.,McPhillie, M.J.,Muench, S.P.,Fishwick, C.W.G.,Sabini, E.,Shanmugam, D.,Roos, D.S.,McLeod, R.,Anderson, W.F.,Ngo, H.M.
CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii .
Front Cell Infect Microbiol, 8:352-352, 2018

PubMed Abstract: , an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.

PubMed: 30345257
DOI: 10.3389/fcimb.2018.00352

実験手法

X-RAY DIFFRACTION (1.2 Å)