9nww | pdb_00009nww
Single-particle cryo-EM structure of the first variant of mobilized colistin resistance (MCR-1) in its ligand-bound state
Structural highlights
FunctionMCR1_ECOLX Probably catalyzes the addition of a phosphoethanolamine moiety to lipid A. Phosphoethanolamine modification of lipid A gives polymyxin resistance (PubMed:26603172).[1] Confers resistance to polymyxin-type antibiotics; expression of the Mcr-1 protein in E.coli increases colistin and polymyxin B minimal inhibitory concentration (MIC) from 0.5 mg/ml to 2.0 mg/ml. The pHNSHP45 plasmid can transfer efficiently (0.1 to 0.001) to other E.coli strains by conjugation and increases polymxin MIC by 8- to 16-fold; it may not require selective pressure to be maintained in the cell. When transformed into K.pneumoniae or P.aeruginosa it also increases polymxin MIC 8- to 16-fold. In a murine (BALB/c mice) thigh infection study using an mcr1-encoding plasmid isolated from a human patient, the plasmid confers in vivo protection against colistin (PubMed:26603172).[2] Publication Abstract from PubMedPolymyxins are used to treat infections caused by multidrug-resistant Gram-negative bacteria. They are cationic peptides that target the negatively charged lipid A component of lipopolysaccharides, disrupting the outer membrane and lysing the cell. Polymyxin resistance is conferred by inner-membrane enzymes, such as phosphoethanolamine transferases, which add positively charged phosphoethanolamine to lipid A. Here, we present the structure of MCR-1, a plasmid-encoded phosphoethanolamine transferase, in its liganded form. The phosphatidylethanolamine donor substrate is bound near the active site in the periplasmic domain, and lipid A is bound over 20 A away, within the transmembrane region. Integrating structural, biochemical, and drug-resistance data with computational analyses, we propose a two-state model in which the periplasmic domain rotates to bring the active site to lipid A, near the preferential phosphate modification site for MCR-1. This enzymatic mechanism may be generally applicable to other phosphoform transferases with large, globular soluble domains. Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1.,Zinkle AP, Batista MB, Herrera CM, Erramilli SK, Kloss B, Ashraf KU, Nosol K, Zhang G, Cater RJ, Marty MT, Kossiakoff AA, Trent MS, Nygaard R, Stansfeld PJ, Mancia F Nat Commun. 2025 Nov 26;16(1):10516. doi: 10.1038/s41467-025-65515-3. PMID:41298376[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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