8PWZ

Crystal Structure of (3R)-hydroxyacyl-ACP dehydratase HadBD from Mycobacterium tuberculosis

Summary for 8PWZ

• Entry DOI: 10.2210/pdb8pwz/pdb
• Descriptor: UPF0336 protein Rv0504c, (3R)-hydroxyacyl-ACP dehydratase subunit HadB (3 entities in total)
• Functional Keywords: (3r)-hydroxyacyl-acp dehydratase, fas-ii system, mycolic acid synthesis, lyase
• Biological source: Mycobacterium tuberculosis H37Rv; More
• Total number of polymer chains: 2
• Total formula weight: 35507.23

Authors

Rima, J.,Grimoire, Y.,Bories, P.,Bardou, F.,Quemard, A.,Bon, C.,Mourey, L.,Tranier, S. (deposition date: 2023-07-22, release date: 2024-03-27)

Primary citation

Bories, P.,Rima, J.,Tranier, S.,Marcoux, J.,Grimoire, Y.,Tomaszczyk, M.,Launay, A.,Fata, K.,Marrakchi, H.,Burlet-Schiltz, O.,Mourey, L.,Ducoux-Petit, M.,Bardou, F.,Bon, C.,Quemard, A.
HadBD dehydratase from Mycobacterium tuberculosis fatty acid synthase type II: A singular structure for a unique function.
Protein Sci., 33:e4964-e4964, 2024

PubMed Abstract: Worldwide, tuberculosis is the second leading infectious killer and multidrug resistance severely hampers disease control. Mycolic acids are a unique category of lipids that are essential for viability, virulence, and persistence of the causative agent, Mycobacterium tuberculosis (Mtb). Therefore, enzymes involved in mycolic acid biosynthesis represent an important class of drug targets. We previously showed that the (3R)-hydroxyacyl-ACP dehydratase (HAD) protein HadD is dedicated mainly to the production of ketomycolic acids and plays a determinant role in Mtb biofilm formation and virulence. Here, we discovered that HAD activity requires the formation of a tight heterotetramer between HadD and HadB, a HAD unit encoded by a distinct chromosomal region. Using biochemical, structural, and cell-based analyses, we showed that HadB is the catalytic subunit, whereas HadD is involved in substrate binding. Based on HadBD crystal structure and substrate-bound models, we identified determinants of the ultra-long-chain lipid substrate specificity and revealed details of structure-function relationship. HadBD unique function is partly due to a wider opening and a higher flexibility of the substrate-binding crevice in HadD, as well as the drastically truncated central α-helix of HadD hotdog fold, a feature described for the first time in a HAD enzyme. Taken together, our study shows that HadBD , and not HadD alone, is the biologically relevant functional unit. These results have important implications for designing innovative antivirulence molecules to fight tuberculosis, as they suggest that the target to consider is not an isolated subunit, but the whole HadBD complex.

PubMed: 38501584
DOI: 10.1002/pro.4964

Experimental method

X-RAY DIFFRACTION (2.00196723217 Å)