3IVT

Homocitrate Synthase Lys4 bound to 2-OG

3IVT の概要

• エントリーDOI: 10.2210/pdb3ivt/pdb
• 関連するPDBエントリー: 3IVS 3IVU
• 分子名称: Homocitrate synthase, mitochondrial, ZINC ION, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: tim barrel, metalloprotein, transferase, claisen condensation, amino-acid biosynthesis, lysine biosynthesis, mitochondrion, transit peptide
• 由来する生物種: Schizosaccharomyces pombe (Fission yeast)
• 細胞内の位置: Mitochondrion : Q9Y823
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93978.98

構造登録者

Bulfer, S.L.,Scott, E.M.,Couture, J.-F.,Pillus, L.,Trievel, R.C. (登録日: 2009-09-01, 公開日: 2009-09-22, 最終更新日: 2024-04-03)

主引用文献

Bulfer, S.L.,Scott, E.M.,Couture, J.F.,Pillus, L.,Trievel, R.C.
Crystal structure and functional analysis of homocitrate synthase, an essential enzyme in lysine biosynthesis.
J.Biol.Chem., 284:35769-35780, 2009

PubMed Abstract: Homocitrate synthase (HCS) catalyzes the first and committed step in lysine biosynthesis in many fungi and certain Archaea and is a potential target for antifungal drugs. Here we report the crystal structure of the HCS apoenzyme from Schizosaccharomyces pombe and two distinct structures of the enzyme in complex with the substrate 2-oxoglutarate (2-OG). The structures reveal that HCS forms an intertwined homodimer stabilized by domain-swapping between the N- and C-terminal domains of each monomer. The N-terminal catalytic domain is composed of a TIM barrel fold in which 2-OG binds via hydrogen bonds and coordination to the active site divalent metal ion, whereas the C-terminal domain is composed of mixed alpha/beta topology. In the structures of the HCS apoenzyme and one of the 2-OG binary complexes, a lid motif from the C-terminal domain occludes the entrance to the active site of the neighboring monomer, whereas in the second 2-OG complex the lid is disordered, suggesting that it regulates substrate access to the active site through its apparent flexibility. Mutations of the active site residues involved in 2-OG binding or implicated in acid-base catalysis impair or abolish activity in vitro and in vivo. Together, these results yield new insights into the structure and catalytic mechanism of HCSs and furnish a platform for developing HCS-selective inhibitors.

PubMed: 19776021
DOI: 10.1074/jbc.M109.046821

実験手法

X-RAY DIFFRACTION (2.67 Å)