9HRA

Crystal Structure of the Coxiella burnetii 2-methylisocitrate lyase Bound to Products Succinic and Pyruvic Acid

9HRA の概要

• エントリーDOI: 10.2210/pdb9hra/pdb
• 関連するPDBエントリー: 9HGK 9HGO 9HGQ 9HHS 9HHY
• 分子名称: 2-methylisocitrate lyase, SUCCINIC ACID, PYRUVIC ACID, ... (10 entities in total)
• 機能のキーワード: prpb, methylisocitrate lyase, carbon-carbon lyase, ec 4.1.3.30, cytosolic protein
• 由来する生物種: Coxiella burnetii
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 256876.79

構造登録者

Stuart, W.,Isupov, M.,Harmer, N.J. (登録日: 2024-12-17, 公開日: 2025-08-13)

主引用文献

Stuart, W.S.,Jenkins, C.H.,Ireland, P.M.,Isupov, M.N.,Norville, I.H.,Harmer, N.J.
Structure and catalytic mechanism of methylisocitrate lyase, a potential drug target against Coxiella burnetii.
J.Biol.Chem., 301:108517-108517, 2025

PubMed Abstract: We present a comprehensive investigation into the catalytic mechanism of methylisocitrate lyase, a potential drug target candidate against the zoonotic pathogen Coxiella burnetii, the causative agent of Q fever and a federal select agent. Current treatment regimens are prolonged, often with incomplete clearance of the pathogen. We utilized a structure-based bioinformatics pipeline to identify methylisocitrate lyase as a candidate therapeutic target against C. burnetii from a list of essential genes. WT C. burnetii methylisocitrate lyase has a k of 13.8 s (compared to 105 s for Salmonella enterica), and isocitrate inhibits with a K of 11 mM. We have determined the previously uncharacterized substrate-bound structure of this enzyme family, alongside product and inhibitor-bound structures. These structures of WT enzyme reveal that in the active state the catalytic C118 is positioned 2.98 Å from O5 of methylisocitrate and Arg152 moves toward the substrate relative to the inhibitor bound structure. Analysis of structure-based mutants reveals that Arg152 and Glu110 are both essential for catalysis. We suggest that Arg152 acts as the catalytic base that initiates the methylisocitrate lyase reaction. These results deepen our understanding of the catalytic mechanism of methylisocitrate lyase and could aid the development of new therapeutics against C. burnetii.

PubMed: 40250561
DOI: 10.1016/j.jbc.2025.108517

実験手法

X-RAY DIFFRACTION (2.48 Å)