4F4Q

Crystal structure of M. smegmatis DprE1 in complex with FAD and covalently bound BTZ043

4F4Q の概要

• エントリーDOI: 10.2210/pdb4f4q/pdb
• 分子名称: DprE1, 8-(hydroxyamino)-2-[(2S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl]-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: fad domain, oxidase, btz043 covalently bound to cys394, oxidoreductase
• 由来する生物種: Mycobacterium smegmatis
• 細胞内の位置: Periplasm : A0R607
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52485.93

構造登録者

Neres, J.,Pojer, F.,Molteni, E.,Chiarelli, L.,Riccardi, G.,Mattevi, A.,Cole, S.T.,Binda, C. (登録日: 2012-05-11, 公開日: 2012-09-05, 最終更新日: 2024-11-27)

主引用文献

Neres, J.,Pojer, F.,Molteni, E.,Chiarelli, L.R.,Dhar, N.,Boy-Rottger, S.,Buroni, S.,Fullam, E.,Degiacomi, G.,Lucarelli, A.P.,Read, R.J.,Zanoni, G.,Edmondson, D.E.,De Rossi, E.,Pasca, M.R.,McKinney, J.D.,Dyson, P.J.,Riccardi, G.,Mattevi, A.,Cole, S.T.,Binda, C.
Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis.
Sci Transl Med, 4:150ra121-150ra121, 2012

PubMed Abstract: The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. BTZ043 targets the DprE1 catalytic component of the essential enzyme decaprenylphosphoryl-β-D-ribofuranose-2'-epimerase, thus blocking biosynthesis of arabinans, vital components of mycobacterial cell walls. Crystal structures of DprE1, in its native form and in a complex with BTZ043, reveal formation of a semimercaptal adduct between the drug and an active-site cysteine, as well as contacts to a neighboring catalytic lysine residue. Kinetic studies confirm that BTZ043 is a mechanism-based, covalent inhibitor. This explains the exquisite potency of BTZ043, which, when fluorescently labeled, localizes DprE1 at the poles of growing bacteria. Menaquinone can reoxidize the flavin adenine dinucleotide cofactor in DprE1 and may be the natural electron acceptor for this reaction in the mycobacterium. Our structural and kinetic analysis provides both insight into a critical epimerization reaction and a platform for structure-based design of improved inhibitors.

PubMed: 22956199
DOI: 10.1126/scitranslmed.3004395

実験手法

X-RAY DIFFRACTION (2.619 Å)