Crystal structure of the essential biotin-dependent carboxylase AccA3 from Mycobacterium tuberculosis
Matthew Bennett, Martin Högbom [1]
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 , and crystallized as a . .
Previous structures have shown defined ‘open’ and ‘closed’ states of the B-domain[2][3]. In addition, the biotin carboxylase domain of pyruvate carboxylase from Bacillus thermodenitrificans displays what appears to be an intermediate, but defined, conformation [4]. In the current structure, however, while represents the previously observed ‘closed’ state, 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.
of biotin and ADP binding in MTb AccA3 based on the biotin and ADP-bound Escherichia coli BDC (PDB 3g8c). Substrate-bridging loop of MTb AccA3 rendered in pink and E. coli BDC in cyan.
Coordinates and structure factors have been deposited in the PDB: 5mlk.
