3MI3

Homocitrate Synthase Lys4 bound to Lysine

Replaces:  3L90

Summary for 3MI3

• Entry DOI: 10.2210/pdb3mi3/pdb
• Related: 3IVS 3IVT 3IVU
• Descriptor: Homocitrate synthase, mitochondrial, LYSINE, ZINC ION, ... (5 entities in total)
• Functional Keywords: tim barrel, metalloprotein, transferase, claisen condensation, amino-acid biosynthesis, lysine biosynthesis
• Biological source: Schizosaccharomyces pombe (Fission yeast)
• Cellular location: Mitochondrion (Potential): Q9Y823
• Total number of polymer chains: 2
• Total formula weight: 93981.17

Authors

Bulfer, S.L.,Scott, E.M.,Pillus, L.,Trievel, R.C. (deposition date: 2010-04-09, release date: 2010-04-28, Last modification date: 2023-09-06)

Primary citation

Bulfer, S.L.,Scott, E.M.,Pillus, L.,Trievel, R.C.
Structural Basis for L-lysine Feedback Inhibition of Homocitrate Synthase
J.Biol.Chem., 285:10446-10453, 2010

PubMed Abstract: The alpha-aminoadipate pathway of lysine biosynthesis is modulated at the transcriptional and biochemical levels by feedback inhibition. The first enzyme in the alpha-aminoadipate pathway, homocitrate synthase (HCS), is the target of the feedback regulation and is strongly inhibited by l-lysine. Here we report the structure of Schizosaccharomyces pombe HCS (SpHCS) in complex with l-lysine. The structure illustrates that the amino acid directly competes with the substrate 2-oxoglutarate for binding within the active site of HCS. Differential recognition of the substrate and inhibitor is achieved via a switch position within the (alpha/beta)(8) TIM barrel of the enzyme that can distinguish between the C5-carboxylate group of 2-oxoglutarate and the epsilon-ammonium group of l-lysine. In vitro and in vivo assays demonstrate that mutations of the switch residues, which interact with the l-lysine epsilon-ammonium group, abrogate feedback inhibition, as do substitutions of residues within the C-terminal domain that were identified in a previous study of l-lysine-insensitive HCS mutants in Saccharomyces cerevisiae. Together, these results yield new insights into the mechanism of feedback regulation of an enzyme central to lysine biosynthesis.

PubMed: 20089861

Experimental method

X-RAY DIFFRACTION (2.38 Å)