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LolCDE in complex with SMT-738_3
Structural highlights
FunctionLOLC_ECOLI Part of an ATP-dependent transport system LolCDE responsible for the release of lipoproteins targeted to the outer membrane from the inner membrane. Such a release is dependent of the sorting-signal (absence of an Asp at position 2 of the mature lipoprotein) and of LolA. Publication Abstract from PubMedSMT-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. Molecular mechanism of action of small molecule SMT-738 on bacterial lipoprotein transporter LolCDE.,Li H, Zhu X, Zhang D, Duan X, Li J, Qu Y, Li D, Zhang Z, Dong H, Guo FB, Dong C Nat Commun. 2026 Feb 9. doi: 10.1038/s41467-026-69411-2. PMID:41663437[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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