4F4Q

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

Summary for 4F4Q

• Entry DOI: 10.2210/pdb4f4q/pdb
• Descriptor: 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)
• Functional Keywords: fad domain, oxidase, btz043 covalently bound to cys394, oxidoreductase
• Biological source: Mycobacterium smegmatis
• Cellular location: Periplasm : A0R607
• Total number of polymer chains: 1
• Total formula weight: 52485.93

Authors

Neres, J.,Pojer, F.,Molteni, E.,Chiarelli, L.,Riccardi, G.,Mattevi, A.,Cole, S.T.,Binda, C. (deposition date: 2012-05-11, release date: 2012-09-05, Last modification date: 2024-11-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.619 Å)