4W1V

Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with a thiazole inhibitor

4W1V の概要

• エントリーDOI: 10.2210/pdb4w1v/pdb
• 関連するPDBエントリー: 4W1W 4W1X
• 分子名称: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, PYRIDOXAL-5'-PHOSPHATE, dimethyl (2R)-5-(3-fluorophenyl)-1H-pyrrolo[1,2-c][1,3]thiazole-6,7-dicarboxylate 2-oxide, ... (7 entities in total)
• 機能のキーワード: inhibitor complex transaminase plp, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cytoplasm : P9WQ80
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 92891.44

構造登録者

Finzel, B.C.,Dai, R. (登録日: 2014-08-13, 公開日: 2015-02-04, 最終更新日: 2023-12-27)

主引用文献

Park, S.W.,Casalena, D.E.,Wilson, D.J.,Dai, R.,Nag, P.P.,Liu, F.,Boyce, J.P.,Bittker, J.A.,Schreiber, S.L.,Finzel, B.C.,Schnappinger, D.,Aldrich, C.C.
Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis.
Chem.Biol., 22:76-86, 2015

PubMed Abstract: Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts.

PubMed: 25556942
DOI: 10.1016/j.chembiol.2014.11.012

実験手法

X-RAY DIFFRACTION (2.24 Å)