7nrf

Crystal structure of E.coli BamA beta-barrel in complex with darobactin (crystal form 2)

spinqualitylabelsall models 7nrf, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7nrf is a 2 chain structure with sequence from Escherichia coli O157:H7 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: C8E, MG, UX8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BAMA_ECOLI Part of the outer membrane protein assembly complex, which is involved in assembly and insertion of beta-barrel proteins into the outer membrane. Constitutes, with BamD, the core component of the assembly machinery. Publication Abstract from PubMed Antibiotics that target Gram-negative bacteria in new ways are needed to resolve the antimicrobial resistance crisis(1-3). Gram-negative bacteria are protected by an additional outer membrane, rendering proteins on the cell surface attractive drug targets(4,5). The natural compound darobactin targets the bacterial insertase BamA(6)-the central unit of the essential BAM complex, which facilitates the folding and insertion of outer membrane proteins(7-13). BamA lacks a typical catalytic centre, and it is not obvious how a small molecule such as darobactin might inhibit its function. Here we resolve the mode of action of darobactin at the atomic level using a combination of cryo-electron microscopy, X-ray crystallography, native mass spectrometry, in vivo experiments and molecular dynamics simulations. Two cyclizations pre-organize the darobactin peptide in a rigid beta-strand conformation. This creates a mimic of the recognition signal of native substrates with a superior ability to bind to the lateral gate of BamA. Upon binding, darobactin replaces a lipid molecule from the lateral gate to use the membrane environment as an extended binding pocket. Because the interaction between darobactin and BamA is largely mediated by backbone contacts, it is particularly robust against potential resistance mutations. Our results identify the lateral gate as a functional hotspot in BamA and will allow the rational design of antibiotics that target this bacterial Achilles heel. The antibiotic darobactin mimics a beta-strand to inhibit outer membrane insertase.,Kaur H, Jakob RP, Marzinek JK, Green R, Imai Y, Bolla JR, Agustoni E, Robinson CV, Bond PJ, Lewis K, Maier T, Hiller S Nature. 2021 May;593(7857):125-129. doi: 10.1038/s41586-021-03455-w. Epub 2021 , Apr 14. PMID:33854236 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bam complex 3D structures

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