3IVU

Homocitrate Synthase Lys4 bound to 2-OG

Summary for 3IVU

• Entry DOI: 10.2210/pdb3ivu/pdb
• Related: 3IVS 3IVT
• Descriptor: Homocitrate synthase, mitochondrial, COBALT (II) ION, SODIUM ION, ... (5 entities in total)
• Functional Keywords: tim barrel, metalloprotein, transferase, claisen condensation, amino-acid biosynthesis, lysine biosynthesis, mitochondrion, transit peptide
• Biological source: Schizosaccharomyces pombe (Fission yeast)
• Cellular location: Mitochondrion : Q9Y823
• Total number of polymer chains: 2
• Total formula weight: 93966.03

Authors

Bulfer, S.L.,Scott, E.M.,Couture, J.-F.,Pillus, L.,Trievel, R.C. (deposition date: 2009-09-01, release date: 2009-09-22, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.72 Å)