8f2l | pdb_00008f2l

Crystal structure of Mycobacterium tuberculosis Homoserine transacetylase in complex with L-Homoserine

spinqualitylabelsall models 8f2l, resolution 2.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8f2l is a 12 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.89Å Ligands: HSE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function METXA_MYCTU Transfers an acetyl group from acetyl-CoA to L-homoserine, forming acetyl-L-homoserine. Publication Abstract from PubMed Mycobacterium tuberculosis (Mtb) lacking functional homoserine transacetylase (HTA) is compromised in methionine biosynthesis, protein synthesis, and in the activity of multiple essential S-adenosyl-l-methionine-dependent enzymes. Additionally, deficient mutants are further disarmed by the toxic accumulation of lysine due to a redirection of the metabolic flux toward the lysine biosynthetic pathway. Studies with deletion mutants and crystallographic studies of the apoenzyme have, respectively, validated Mtb HTA as an essential enzyme and revealed a ligandable binding site. Seeking a mechanistic characterization of this enzyme, we report crucial structural details and comprehensive functional characterization of Mtb HTA. Crystallographic and mass spectral observation of the acetylated HTA intermediate and initial velocity studies were consistent with a ping-pong kinetic mechanism. Wild-type HTA and its site-directed mutants were kinetically characterized with a panel of natural and alternative substrates to understand substrate specificity and identify critical residues for catalysis. Titration experiments using fluorescence quenching showed that both substrates horizontal line acetyl-CoA and l-homoserine horizontal line engage in a strong and weak binding interaction with HTA. Additionally, substrate inhibition by acetyl-CoA and product inhibition by CoA and O-acetyl-l-homoserine were proposed to form the basis of a feedback regulation mechanism. By furnishing key mechanistic and structural information, these studies provide a foundation for structure-based design efforts around this attractive Mtb target. Structural and Functional Characterization of Mycobacterium tuberculosis Homoserine Transacetylase.,Sharma S, Jayasinghe YP, Mishra NK, Orimoloye MO, Wong TY, Dalluge JJ, Ronning DR, Aldrich CC ACS Infect Dis. 2023 Feb 8. doi: 10.1021/acsinfecdis.2c00541. PMID:36753622 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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