5TE2

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

5TE2 の概要

• エントリーDOI: 10.2210/pdb5te2/pdb
• 関連するPDBエントリー: 3TFT 3TFU 4CXQ
• 分子名称: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, [5-hydroxy-4-({[6-(3-hydroxypropyl)-4-oxo-1,4-dihydropyridin-3-yl]amino}methyl)-6-methylpyridin-3-yl]methyl dihydrogen phosphate, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: inhibitor complex, transaminase, plp, transferase, transferase-inhibitor complex, mechanism-based inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium bovis (strain ATCC BAA-935 / AF2122/97)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 98190.07

構造登録者

Maize, K.M.,Eiden, C.,Aldrich, C.C.,Finzel, B.C. (登録日: 2016-09-20, 公開日: 2017-05-31, 最終更新日: 2023-10-04)

主引用文献

Eiden, C.G.,Maize, K.M.,Finzel, B.C.,Lipscomb, J.D.,Aldrich, C.C.
Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation.
J. Am. Chem. Soc., 139:7132-7135, 2017

PubMed Abstract: Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine because of their exquisite specificity and sustained duration of inhibition. Optimization of MBIs is complicated because of time-dependent inhibition resulting from multistep inactivation mechanisms. The global kinetic parameters k and K have been used to characterize MBIs, but they provide far less information than is commonly assumed, as shown by derivation and simulation of these parameters. We illustrate an alternative and more rigorous approach for MBI characterization through determination of the individual microscopic rate constants. Kinetic analysis revealed the rate-limiting step of inactivation of the PLP-dependent enzyme BioA by dihydro-(1,4)-pyridone 1. This knowledge was subsequently applied to rationally design a second-generation inhibitor scaffold with a nearly optimal maximum inactivation rate (0.48 min).

PubMed: 28510452
DOI: 10.1021/jacs.7b00962

実験手法

X-RAY DIFFRACTION (1.8 Å)