4WYC

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

4WYC の概要

• エントリーDOI: 10.2210/pdb4wyc/pdb
• 関連するPDBエントリー: 4WYA 4WYD 4WYE 4WYF 4WYG
• 分子名称: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, PYRIDOXAL-5'-PHOSPHATE, 4-(1H-imidazol-1-yl)benzamide, ... (8 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 : P9WQ81
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 98216.25

構造登録者

Finzel, B.C.,Dai, R.,Geders, T.W. (登録日: 2014-11-17, 公開日: 2015-07-08, 最終更新日: 2023-09-27)

主引用文献

Dai, R.,Geders, T.W.,Liu, F.,Park, S.W.,Schnappinger, D.,Aldrich, C.C.,Finzel, B.C.
Fragment-Based Exploration of Binding Site Flexibility in Mycobacterium tuberculosis BioA.
J.Med.Chem., 58:5208-5217, 2015

PubMed Abstract: The PLP-dependent transaminase (BioA) of Mycobacterium tuberculosis and other pathogens that catalyzes the second step of biotin biosynthesis is a now well-validated target for antibacterial development. Fragment screening by differential scanning fluorimetry has been performed to discover new chemical scaffolds and promote optimization of existing inhibitors. Calorimetry confirms binding of six molecules with high ligand efficiency. Thermodynamic data identifies which molecules bind with the enthalpy driven stabilization preferred in compounds that represent attractive starting points for future optimization. Crystallographic characterization of complexes with these molecules reveals the dynamic nature of the BioA active site. Different side chain conformational states are stabilized in response to binding by different molecules. A detailed analysis of conformational diversity in available BioA structures is presented, resulting in the identification of two states that might be targeted with molecular scaffolds incorporating well-defined conformational attributes. This new structural data can be used as part of a scaffold hopping strategy to further optimize existing inhibitors or create new small molecules with improved therapeutic potential.

PubMed: 26068403
DOI: 10.1021/acs.jmedchem.5b00092

実験手法

X-RAY DIFFRACTION (1.7 Å)