Crystal Structure of the Catalytic Domain of MCR-1 (cMCR-1) in Complex with d-Xylose

The polymyxin colistin is known as a “last resort” antibacterial drug toward pandrug-resistant enterobacteria. The recently discovered plasmid-encoded mcr-1 gene spreads rapidly across pathogenic strains and confers resistance to colistin, which has emerged as a global threat. The mcr-1 gene encodes a phosphoethanolamine transferase (MCR-1) that catalyzes the transference of phosphoethanolamine to lipid A moiety of lipopolysaccharide, resulting in resistance to colistin. Development of effective MCR-1 inhibitors is crucial for combating MCR-1-mediated colistin resistance. In this study, MCR-1 catalytic domain (namely cMCR-1) was expressed and co-crystallized together with d-xylose. X-ray crystallographic study at a resolution of 1.8 A found that cMCR-1-d-xylose co-crystals fell under space group P212121, with unit-cell parameters a = 51.6 A, b = 73.1 A, c = 82.2 A, α = 90°, β = 90°, γ = 90°. The asymmetric unit contained a single cMCR-1 molecule complexed with d-xylose and had a solvent content of 29.13%. The structural model of cMCR-1-d-xylose complex showed that a d-xylose molecule bound in the putative lipid A-binding pocket of cMCR-1, which might provide a clue for MCR-1 inhibitor development.