Fig. 1: The role of MCR-1 in conferring polymyxin resistance in Gram-negative bacteria and the structure of MCR-1.

a Schematic representation of polymyxin sensitivity, on left, and polymyxin resistance, on right, showing modification of lipid A (dark red) with PEtN (small orange circle) by MCR-1 (blue/green) and the transport of modified lipid A from the inner membrane to the outer membrane, electrostatically repelling polymyxins. PE donor substrate is shown as a yellow circle with a smaller orange circle and with two lines to represent acyl chains. Individual polymyxin molecules are depicted as purple spheres attached to a small tail and carrying a positive charge. b Cryo-EM density map of the PE- and KLA-bound MCR-1–Fab complex. Density corresponding to the Fab is shown in gray, and the PD and TM domain of MCR-1 are colored green and blue, respectively. The density for KLA is in red, and the density for PE in yellow. c Schematic diagram showing the topology of MCR-1, which consists of five TM helices and a BH connecting the N-terminal TM domain to a large C-terminal PD. Two periplasmic-facing loops, each containing two small α-helices, are present between TM3/4 (PH2/PH2’) and TM5/BH (PH3/PH4). d The 3.6 Å cryo-EM structure of PE- and KLA-bound MCR-1 shown in two different orientations, colored as in (c) The N and C termini are labeled. On the right, the structure has been rotated 90°, as viewed from the top, with helices numbered and the PD removed. PE is shown as sticks in yellow under semi-transparent density. KLA, colored red, is also shown as sticks and under semi-transparent density. The distance measured between the phosphate of PE and the nearest phosphate group belonging to KLA (1-phosphate) is shown as a black dashed line. Nitrogen, oxygen, and phosphorus atoms shown in sticks are colored blue, red, and orange, respectively.