4LV4

A noncompetitive inhibitor for M. tuberculosis's class IIa fructose 1,6-bisphosphate aldolase

4LV4 の概要

• エントリーDOI: 10.2210/pdb4lv4/pdb
• 関連するPDBエントリー: 3EKL 3EKZ 3ELF 4A21 4A22 4DEF 4DEL
• 分子名称: Fructose-bisphosphate aldolase, ZINC ION, 8-hydroxyquinoline-2-carboxylic acid, ... (6 entities in total)
• 機能のキーワード: class ii fructose-1, 6-bisphosphate aldolase, zinc enzyme, mycobacterium tuberculosis, dihydroxyacetone, glyceraldehyde-3-phosphate, aldol condensation, glycolysis, lyase, metal-binding, 8-hydroxyquinoline-2-carboxylic acid, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37952.46

構造登録者

Capodagli, G.C.,Pegan, S.D. (登録日: 2013-07-25, 公開日: 2014-01-08, 最終更新日: 2023-09-20)

主引用文献

Capodagli, G.C.,Sedhom, W.G.,Jackson, M.,Ahrendt, K.A.,Pegan, S.D.
A Noncompetitive Inhibitor for Mycobacterium tuberculosis's Class IIa Fructose 1,6-Bisphosphate Aldolase.
Biochemistry, 53:202-213, 2014

PubMed Abstract: Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 ± 1 μM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates.

PubMed: 24325645
DOI: 10.1021/bi401022b

実験手法

X-RAY DIFFRACTION (2.08 Å)