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Lookup NU author(s): Dr Alistair BrownORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The intracellular pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis, which is a leading cause of mortality worldwide. The survival of M. tuberculosis in host macrophages through long-lasting periods of persistence depends, in part, on breaking down host cell lipids as a carbon source. The critical role of fatty-acid catabolism in this organism is underscored by the extensive redundancy of the genes implicated in β-oxidation (∼100 genes). In a previous study, the enzymology of the M. tuberculosis L-3-hydroxyacyl-CoA dehydrogenase FadB2 was characterized. Here, the crystal structure of this enzyme in a ligand-free form is reported at 2.1 Å resolution. FadB2 crystallized as a dimer with three unique dimer copies per asymmetric unit. The structure of the monomer reveals a dual Rossmann-fold motif in the N-terminal domain, while the helical C-terminal domain mediates dimer formation. Comparison with the CoA- and NAD+-bound human orthologue mitochondrial hydroxyacyl-CoA dehydrogenase shows extensive conservation of the residues that mediate substrate and cofactor binding. Superposition with the multi-catalytic homologue M. tuberculosis FadB, which forms a trifunctional complex with the thiolase FadA, indicates that FadB has developed structural features that prevent its self-association as a dimer. Conversely, FadB2 is unable to substitute for FadB in the tetrameric FadA–FadB complex as it lacks the N-terminal hydratase domain of FadB. Instead, FadB2 may functionally (or physically) associate with the enoyl-CoA hydratase EchA8 and the thiolases FadA2, FadA3, FadA4 or FadA6 as suggested by interrogation of the STRING protein-network database.
Author(s): Cox JAG, Taylor RC, Brown AK, Attoe S, Besra GS, Futterer k
Publication type: Article
Publication status: Published
Journal: Acta Crystallographica Section D Structural Biology
Year: 2019
Volume: 75
Issue: 1
Pages: 101-108
Online publication date: 08/01/2019
Acceptance date: 04/12/2018
Date deposited: 17/01/2019
ISSN (electronic): 2059-7983
Publisher: Wiley
URL: https://doi.org/10.1107/S2059798318017242
DOI: 10.1107/S2059798318017242
PubMed id: 30644849
Notes: PDB reference: FadB2, 6hrd *Correspondence e-mail: k.futterer@bham.ac.uk
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