9EGC

AclA from Tenacibaculum discolor in complex with the C8-N-acyl cyclolysine reaction product (C8-ACL)

This is a non-PDB format compatible entry.

Summary for 9EGC

• Entry DOI: 10.2210/pdb9egc/pdb
• Related: 9EGB 9EGD
• Descriptor: THIF-type NAD/FAD binding fold domain-containing protein, N-[(3R)-2-oxoazepan-3-yl]octanamide, MALEIC ACID, ... (5 entities in total)
• Functional Keywords: n-acyl-cyclolysine, biosynthesis, signaling, transferase
• Biological source: Tenacibaculum discolor
• Total number of polymer chains: 7
• Total formula weight: 213517.69

Authors

Shirkey, J.D.,Jeffrey, P.D.,Linares-Otoya, L.,Khatri Chhetri, B.,Donia, M.S.,Hughson, F.M. (deposition date: 2024-11-21, release date: 2025-08-13, Last modification date: 2025-09-03)

Primary citation

Linares-Otoya, L.,Shirkey, J.D.,Chhetri, B.K.,Mira, A.,Biswas, A.,Neff, S.L.,Linares-Otoya, M.V.,Chen, Y.,Campos-Florian, J.V.,Ganoza-Yupanqui, M.L.,Jeffrey, P.D.,Hughson, F.M.,Donia, M.S.
Discovery of a widespread chemical signalling pathway in the Bacteroidota.
Nature, 2025

PubMed Abstract: Considerable advances have been made in characterizing bioactive molecules secreted by bacteria, yet the regulatory elements controlling their production remain largely understudied. Here we identify and characterize the N-acyl-cyclolysine (ACL) system-a cell-density-dependent chemical signalling system specific to and widespread in the phylum Bacteroidota (formerly Bacteroidetes)-and show that it regulates the expression of co-localized operons encoding diverse secreted molecules. Using genetic and biochemical analyses, combined with structural studies of a key biosynthetic enzyme, AclA, we elucidate the molecular structure of various ACLs and their complete biosynthetic pathway involving L-lysine acylation and ATP-dependent cyclization. Furthermore, we find that secreted ACLs are sensed by a dedicated transcription factor, AclR, resulting in the expression of associated operons and the autoinduction of ACL biosynthesis. Moreover, we show that different Bacteroidota strains produce structurally diverse ACLs and encode transcription factors with varying ligand specificities. Finally, we find that the acl circuit is widely distributed and transcribed in human gut and oral microbiome samples, with clear evidence for an active role in regulating associated operons under host colonization conditions. Understanding the function of the ACL system in different contexts has the potential to reveal details about the biology, ecology and chemistry of the Bacteroidota and how members of this phylum interact with their environments and hosts.

PubMed: 40836091
DOI: 10.1038/s41586-025-09418-9

Experimental method

X-RAY DIFFRACTION (2.55 Å)