5ESS

Crystal Structure of M. tuberculosis MenD bound to Mg2+ and covalent intermediate I (a ThDP and decarboxylated 2-oxoglutarate adduct)

5ESS の概要

• エントリーDOI: 10.2210/pdb5ess/pdb
• 関連するPDBエントリー: 5ERX 5ERY 5ESD 5ESO 5ESU
• 分子名称: 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase, MAGNESIUM ION, FORMIC ACID, ... (8 entities in total)
• 機能のキーワード: menaquinone biosynthesis, mend, 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase, thiamin-diphosphate dependent enzyme, pyruvate oxidase family, transferase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 242304.90

構造登録者

Johnston, J.M.,Jirgis, E.N.M.,Bashiri, G.,Bulloch, E.M.M.,Baker, E.N. (登録日: 2015-11-17, 公開日: 2016-06-22, 最終更新日: 2024-03-06)

主引用文献

Jirgis, E.N.,Bashiri, G.,Bulloch, E.M.,Johnston, J.M.,Baker, E.N.
Structural Views along the Mycobacterium tuberculosis MenD Reaction Pathway Illuminate Key Aspects of Thiamin Diphosphate-Dependent Enzyme Mechanisms.
Structure, 24:1167-1177, 2016

PubMed Abstract: Menaquinone (MQ) is an essential component of the respiratory chains of many pathogenic organisms, including Mycobacterium tuberculosis (Mtb). The first committed step in MQ biosynthesis is catalyzed by 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase (MenD), a thiamin diphosphate (ThDP)-dependent enzyme. Catalysis proceeds through two covalent intermediates as the substrates 2-oxoglutarate and isochorismate are successively added to the cofactor before final cleavage of the product. We have determined a series of crystal structures of Mtb-MenD that map the binding of both substrates, visualizing each step in the MenD catalytic cycle, including both intermediates. ThDP binding induces a marked asymmetry between the coupled active sites of each dimer, and possible mechanisms of communication can be identified. The crystal structures also reveal conformational features of the two intermediates that facilitate reaction but prevent premature product release. These data fully map chemical space to inform early-stage drug discovery targeting MenD.

PubMed: 27291649
DOI: 10.1016/j.str.2016.04.018

実験手法

X-RAY DIFFRACTION (2.2 Å)