Journal:FEBS Open Bio:1

spinqualitylabelsall models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Crystal structure of the essential biotin-dependent carboxylase AccA3 from Mycobacterium tuberculosis Matthew Bennett, Martin Högbom Molecular Tour Biotin-dependent acetyl-CoA carboxylases catalyze the committed step in type II fatty acid biosynthesis, the main route for production of membrane phospholipids in bacteria, and are considered a key target for antibacterial drug discovery. Here we describe the first structure of AccA3, an essential component of the acetyl-CoA carboxylase system in Mycobacterium tuberculosis (MTb). The structure, sequence comparisons, and modeling of ligand-bound states reveal that the ATP cosubstrate-binding site shows distinct differences compared to other bacterial and eukaryotic biotin carboxylases, including all human homologs. This suggests the possibility to design MTb AccA3 subtype-specific inhibitors. Mycobacterium tuberculosis AccA3 adopts the ATPgrasp superfamily fold, and crystallized as a dimer in the asymmetric unit. The lack of an ordered structure for domain B in chain B. Previous structures have shown defined ‘open’ and ‘closed’ states of the B-domain. In addition, the biotin carboxylase domain of pyruvate carboxylase from Bacillus thermodenitrificans displays what appears to be an intermediate, but defined, conformation . In the current structure, however, while protomer A represents the previously observed ‘closed’ state, protomer B represent a different structural state where no conformation is present in high enough occupancy to be possible to reliably model. MTb AccA3, subunit A (blue) and subunit B (yellow), unbound BDC from Escherichia coli (gray) (PDB 1bnc). Based on the location of the segment of positive difference density relative to protomer B, it is, however, clear that the location of the B-domain in the partially occupied structural state that gives rise to this density is not the same as either the previously described ‘closed’ or ‘open’ states. Rather, the density suggests an even more extended conformation of the B-domain relative to the rest of the protein. Together, the most likely interpretation of the combined structural data of biotin-dependent carboxylases is that the B-domain is dynamic over a continuum of conformations, or several defined conformations.

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