9XRO

LolCDE in complex with SMT-738_3

This is a non-PDB format compatible entry.

Summary for 9XRO

• Entry DOI: 10.2210/pdb9xro/pdb
• EMDB information: 67153
• Descriptor: Lipoprotein-releasing system transmembrane protein LolC, Lipoprotein-releasing system transmembrane protein LolE, Lipoprotein-releasing system ATP-binding protein LolD, ... (4 entities in total)
• Functional Keywords: bacterial lipoprotein transporter, lolcde inhibitor, cryo-em, allosteric conformational change, transport protein
• Biological source: Escherichia coli K-12; More
• Total number of polymer chains: 3
• Total formula weight: 115650.41

Authors

Dong, C.J.,Li, H.T. (deposition date: 2025-11-19, release date: 2026-03-18)

Primary citation

Li, H.,Zhu, X.,Zhang, D.,Duan, X.,Li, J.,Qu, Y.,Li, D.,Zhang, Z.,Dong, H.,Guo, F.B.,Dong, C.
Molecular mechanism of action of small molecule SMT-738 on bacterial lipoprotein transporter LolCDE.
Nat Commun, 2026

PubMed Abstract: SMT-738 is a small molecule with promising antibacterial activity against Enterobacteriaceae, including multi-drug-resistant Escherichia coli. Mutations in genes encoding the lipoprotein transport complex (LolCDE) confer resistance to SMT-738. Here, we report the cryogenic electron microscopy structure of the LolCDE-SMT-738 complex at a high resolution. We use mutagenesis, drug resistance assays, biochemical assays, and molecular dynamics simulations to show that SMT-738 binds to the periplasmic end of the LolCE transmembrane domains. This binding induces an allosteric conformational change in the cytoplasmic end of the LolCE transmembrane domains and the coupling helices, leading to dissociation of one LolD subunit from the LolCDE complex. This structural disruption results in a "deadlock" of the LolCDE complex, rendering a transport-incompetent state. Our findings also provide insights into the mechanism of SMT-738 resistance and selectivity.

PubMed: 41663437
DOI: 10.1038/s41467-026-69411-2

Experimental method

ELECTRON MICROSCOPY (2.88 Å)