9D30

Cryo-EM structure of mycocerosic acid synthase with a single DH-ACP crosslink using C16 alpha-bromoamide. Complex C

Summary for 9D30

• Entry DOI: 10.2210/pdb9d30/pdb
• EMDB information: 46506
• Descriptor: Mycocerosic acid synthase, N-[2-(hexadecanoylamino)ethyl]-N~3~-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-beta-alaninamide (2 entities in total)
• Functional Keywords: fas, polyketide, crosslinked, dehydratase, biosynthetic protein
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 452845.05

Authors

Heberlig, G.W.,Jiang, Z.,Burkart, M.D. (deposition date: 2024-08-09, release date: 2025-08-13, Last modification date: 2025-09-03)

Primary citation

Jiang, Z.,Heberlig, G.W.,Chen, J.A.,Huynh, J.,La Clair, J.J.,Burkart, M.D.
Visualizing acyl carrier protein interactions within a crosslinked type I polyketide synthase.
Nat Commun, 16:7798-7798, 2025

PubMed Abstract: Using a combination of dual covalent crosslinking and cryo-EM analyses, we elucidate the structure of mycocerosic acid synthase from Mycobacterium tuberculosis trapped in two distinct catalytic states during its iterative cycle. These structures reveal domain architecture of the acyl carrier protein mediating condensation and dehydration through dual site-selective crosslinking of the acyl carrier protein with the ketosynthase and dehydratase domains. Map density was sufficient to visualize full domain architecture with active site-bound probes and elucidate key interactions of four distinct crosslinked species. Here, iterative vectorial polyketide biosynthesis arises through an overall twisting and tilting architecture, enabling positioning and entry of the cognate substrate at each enzymatic domain. These structures present valuable details for future therapeutic design against mycocerosic acid biosynthesis in M. tuberculosis.

PubMed: 40841798
DOI: 10.1038/s41467-025-63024-x

Experimental method

ELECTRON MICROSCOPY (3.74 Å)