6VB9

Covalent adduct of cis-2,3-epoxysuccinic acid with Isocitrate Lyase-1 from Mycobacterium tuberculosis

6VB9 の概要

• エントリーDOI: 10.2210/pdb6vb9/pdb
• 分子名称: Isocitrate lyase, MAGNESIUM ION, OXALIC ACID, ... (6 entities in total)
• 機能のキーワード: enzyme, covalent inhibitor, substrate analog, structural genomics, psi-biology, tb structural genomics consortium, tbsgc, lyase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 191477.95

構造登録者

Krieger, I.V.,Pham, T.V.,Meek, T.D.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (登録日: 2019-12-18, 公開日: 2020-12-30, 最終更新日: 2023-10-11)

主引用文献

Pham, T.V.,Mellott, D.M.,Moghadamchargari, Z.,Chen, K.,Krieger, I.,Laganowsky, A.,Sacchettini, J.C.,Meek, T.D.
Covalent Inactivation of Mycobacterium tuberculosis Isocitrate Lyase by cis -2,3-Epoxy-Succinic Acid.
Acs Chem.Biol., 16:463-470, 2021

PubMed Abstract: The isocitrate lyases (ICL1/2) are essential enzymes of (), the causative agent of tuberculosis. At present, no ICL1/2 inhibitors have progressed to clinical evaluation, despite extensive drug discovery efforts. Herein, we surveyed succinate analogs against ICL1 and found that dicarboxylic acids constrained in their conformations, such as maleic acid, comprise uncompetitive inhibitors of ICL1 and inhibit more potently than their -isomers. From this, we identified -2,3 epoxysuccinic acid (-EpS) as a selective, irreversible covalent inactivator of ICL1 (/= (5.0 ± 1.4) × 10 M s; = 200 ± 50 nM), the most potent inactivator of ICL1 yet characterized. Crystallographic and mass spectrometric analysis demonstrated that Cys of ICL1 was S-malylated by -EpS, and a crystallographic "snapshot" of inactivation lent insight into the chemical mechanism of this inactivation. Proteomic analysis of lysates showed that -EpS selectively labeled plasmid-expressed ICL1. Consistently, -EpS, but not its -isomer, inhibited the growth of under conditions in which ICL function is essential. These findings encourage the development of analogs of -2,3-epoxysuccinate as antituberculosis agents.

PubMed: 33688722
DOI: 10.1021/acschembio.0c00740

実験手法

X-RAY DIFFRACTION (1.881 Å)