6VO2

Crystal structure of Staphylococcus aureus ketol-acid reductoisomerase in complex with Mg, NADPH and inhibitor.

6VO2 の概要

• エントリーDOI: 10.2210/pdb6vo2/pdb
• 分子名称: Ketol-acid reductoisomerase (NADP(+)), MAGNESIUM ION, 3-(methylsulfonyl)-2-oxopropanoic acid, ... (5 entities in total)
• 機能のキーワード: reductoisomerase, inhibitor, complex, metal binding protein
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76035.91

構造登録者

Bayaraa, T.,Patel, K.M.,Guddat, L.W. (登録日: 2020-01-29, 公開日: 2020-04-08, 最終更新日: 2023-10-11)

主引用文献

Bayaraa, T.,Kurz, J.L.,Patel, K.M.,Hussein, W.M.,Bilyj, J.K.,West, N.P.,Schenk, G.,McGeary, R.P.,Guddat, L.W.
Discovery, Synthesis and Evaluation of a Ketol-Acid Reductoisomerase Inhibitor.
Chemistry, 26:8958-8968, 2020

PubMed Abstract: Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis. Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis (Mt) KARI and identified two compounds that have K values below 200 nm. In Mt cell susceptibility assays one of these compounds exhibited an IC value of 0.8 μm. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2H-benzo[b][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56 % identity with Mt KARI, NADPH and Mg yielded a structure to 1.72 Å resolution. However, only a hydrolyzed product of the inhibitor (i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, 3-(methylsulfonyl)-2-oxopropanic acid was identified as a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data.

PubMed: 32198779
DOI: 10.1002/chem.202000899

実験手法

X-RAY DIFFRACTION (1.59 Å)