9PL0

The structure of the Fusobacterium nucleatum Enoyl-Acyl Carrier Protein Reductase (FabK) bound to an inhibitor

This is a non-PDB format compatible entry.

Summary for 9PL0

• Entry DOI: 10.2210/pdb9pl0/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase, FLAVIN MONONUCLEOTIDE, SODIUM ION, ... (8 entities in total)
• Functional Keywords: fabk, fusobacterium nucleatum, enoyl-acyl carrier protein reductase, fas-ii pathway, oxidoreductase
• Biological source: Fusobacterium nucleatum
• Total number of polymer chains: 12
• Total formula weight: 457361.48

Authors

Alaidi, O.,Avad, K.,Hevener, K. (deposition date: 2025-07-15, release date: 2026-01-28, Last modification date: 2026-03-11)

Primary citation

Avad, K.,Alaidi, O.,Okpomo, D.,Pavel, F.B.A.,Doran, D.,Matheson, M.,Sun, D.,Hurdle, J.,Hevener, K.E.
Structural and Biochemical Characterization of Fusobacterium nucleatum Enoyl-ACP Reductase II (FabK) Reveals the Basis for Bacterial Species-Specific Inhibition.
Acs Bio Med Chem Au, 6:44-55, 2026

PubMed Abstract: is a Gram-negative anaerobic bacterium ubiquitous in the oral cavity and increasingly recognized for its involvement in diverse clinical conditions, including periodontal disease, inflammatory bowel disease, premature birth, and several forms of cancer. These associations highlight the need for narrow-spectrum antibacterial agents directed against to avoid disruption of beneficial microflora and limit the rise of antibiotic resistance. Recent studies have identified the fusobacterial fatty acid synthesis pathway (FAS-II) enzyme, enoyl-acyl carrier protein (ACP) reductase, FabK, as an essential and promising target for selective antibacterial intervention. However, there is a lack of detailed structural information, which has hindered the validation of FabK's druggability and the discovery of new inhibitors. Here, we present a comprehensive characterization of FabK, including its cocrystal structure solved at 2.25 Å resolution and its biochemical and biophysical interactions with a series of potent small-molecule inhibitors. Our analyses revealed that these inhibitors display low to submicromolar activity against FabK, with notable selectivity and differential activity when tested against FabK homologues from other bacterial pathogens. Importantly, the unique structural features of the FabK active site, elucidated through these crystallographic studies, provide a mechanistic basis for species-specific inhibition. These findings not only validate FabK as a druggable target but also furnish critical insights into the design of next-generation narrow-spectrum antibacterial agents.

PubMed: 41726333
DOI: 10.1021/acsbiomedchemau.5c00199

Experimental method

X-RAY DIFFRACTION (2.25 Å)