2O0R

The three-dimensional structure of N-Succinyldiaminopimelate aminotransferase from Mycobacterium tuberculosis

2O0R の概要

• エントリーDOI: 10.2210/pdb2o0r/pdb
• 分子名称: Rv0858c (N-Succinyldiaminopimelate aminotransferase), CHLORIDE ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: plp-binding enzyme, lysine biosynthesis, aminotransferase, structural genomics, tb structural genomics consortium, tbsgc, transferase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88455.73

構造登録者

Weyand, S.,Kefala, G.,Weiss, M.S.,TB Structural Genomics Consortium (TBSGC) (登録日: 2006-11-28, 公開日: 2007-02-27, 最終更新日: 2023-11-15)

主引用文献

Weyand, S.,Kefala, G.,Weiss, M.S.
The Three-dimensional Structure of N-Succinyldiaminopimelate Aminotransferase from Mycobacterium tuberculosis
J.Mol.Biol., 367:825-838, 2007

PubMed Abstract: Inhibitors of the enzymes of the lysine biosynthetic pathway are considered promising lead compounds for the design of new antibacterial drugs, because the pathway appears to be indispensable for bacteria and because it is absent in humans. As part of our efforts to structurally characterize all enzymes of this pathway in Mycobacterium tuberculosis (Mtb), we have determined the three-dimensional structure of N-succinyldiaminopimelate aminotransferase (DapC, DAP-AT, Rv0858c) to a resolution of 2.0 A. This structure is the first DAP-AT structure reported to date. The orthorhombic crystals of Mtb-DAP-AT contain one functional dimer exhibiting C(2) symmetry in the asymmetric unit. The homodimer displays the typical S-shape of class I pyridoxal-5'-phosphate (PLP)-binding proteins. The two active sites of the dimer both feature an internal aldimine with the co-factor PLP covalently bound to the Lys232, although neither substrate nor co-factor had been added during protein production, purification and crystallization. Nine water molecules are conserved in the active site and form an intricate hydrogen-bonding network with the co-factor and the surrounding amino acid residues. Together with some residual difference electron density in the active site, this architecture permitted the building of external aldimine models of the enzyme with the substrates glutamate, the amine donor, and N-succinyl-2-amino-6-keto-pimelate, the amine acceptor. Based on these models, the amino acids relevant for substrate binding and specificity can be postulated. Furthermore, in the external aldimine model of N-succinyl-2-amino-6-keto-pimelate, the succinyl group overlaps with a glycerol binding site that has also been identified in both active sites of the Mtb-DAP-AT dimer. A comparison of the structure of Mtb-DAP-AT with other class I PLP-binding proteins, revealed that some inhibitors utilize the same binding site. Thus, the proposed models also provide an explanation for the mode of inhibition of Mtb-DAP-AT and they may be of help in the design of compounds, which are capable of inhibiting the enzyme. Last, but not least, a chloride binding helix exhibiting a peculiar amino acid sequence with a number of exposed hydrophobic side-chains was identified, which may be hypothesized as a putative docking site.

PubMed: 17292400
DOI: 10.1016/j.jmb.2007.01.023

実験手法

X-RAY DIFFRACTION (2 Å)