5I5Y

X-RAY CRYSTAL STRUCTURE AT 1.81A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH AN ARYL ACETATE COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.

5I5Y の概要

• エントリーDOI: 10.2210/pdb5i5y/pdb
• 関連するPDBエントリー: 5I5S 5I5T 5I5U 5I5V 5I5W 5I5X 5I60
• 分子名称: Branched-chain-amino-acid aminotransferase, mitochondrial, PYRIDOXAL-5'-PHOSPHATE, {2-[(5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbonyl)amino]phenyl}acetic acid, ... (7 entities in total)
• 機能のキーワード: fold type iv, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform A: Mitochondrion. Isoform B: Cytoplasm: O15382
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85424.30

構造登録者

Somers, D.O. (登録日: 2016-02-15, 公開日: 2016-03-23, 最終更新日: 2024-05-01)

主引用文献

Borthwick, J.A.,Ancellin, N.,Bertrand, S.M.,Bingham, R.P.,Carter, P.S.,Chung, C.W.,Churcher, I.,Dodic, N.,Fournier, C.,Francis, P.L.,Hobbs, A.,Jamieson, C.,Pickett, S.D.,Smith, S.E.,Somers, D.O.,Spitzfaden, C.,Suckling, C.J.,Young, R.J.
Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.
J.Med.Chem., 59:2452-2467, 2016

PubMed Abstract: Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility.

PubMed: 26938474
DOI: 10.1021/acs.jmedchem.5b01607

実験手法

X-RAY DIFFRACTION (1.81 Å)