9NWW

Single-particle cryo-EM structure of the first variant of mobilized colistin resistance (MCR-1) in its ligand-bound state

Summary for 9NWW

• Entry DOI: 10.2210/pdb9nww/pdb
• EMDB information: 49896
• Descriptor: Probable phosphatidylethanolamine transferase Mcr-1, Fab (MR6) Light (L) Chain, Fab (MR6) Heavy (H) Chain, ... (5 entities in total)
• Functional Keywords: membrane protein, phosphoethanolamine transferase, lipid a modification, polymyxin resistance, transferase
• Biological source: Escherichia coli; More
• Total number of polymer chains: 3
• Total formula weight: 115280.21

Authors

Zinkle, A.P.,Bunuro-Batista, M.,Herrera, C.M.,Erramilli, S.K.,Kloss, B.,Ashraf, K.U.,Nosol, K.,Zhang, G.,Cater, R.J.,Marty, M.T.,Kossiakoff, A.A.,Trent, M.S.,Nygaard, R.,Stansfeld, P.J.,Mancia, F. (deposition date: 2025-03-24, release date: 2025-12-17)

Primary citation

Zinkle, A.P.,Batista, M.B.,Herrera, C.M.,Erramilli, S.K.,Kloss, B.,Ashraf, K.U.,Nosol, K.,Zhang, G.,Cater, R.J.,Marty, M.T.,Kossiakoff, A.A.,Trent, M.S.,Nygaard, R.,Stansfeld, P.J.,Mancia, F.
Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1.
Nat Commun, 16:10516-10516, 2025

PubMed Abstract: Polymyxins 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 Å 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.

PubMed: 41298376
DOI: 10.1038/s41467-025-65515-3

Experimental method

ELECTRON MICROSCOPY (3.58 Å)