5YLF

MCR-1 complex with D-glucose

Summary for 5YLF

• Entry DOI: 10.2210/pdb5ylf/pdb
• Related: 5YLC 5YLE
• Descriptor: Probable phosphatidylethanolamine transferase Mcr-1, beta-D-glucopyranose, ZINC ION, ... (4 entities in total)
• Functional Keywords: phosphoethanolamine transferase, plasmid-mediated transferable colistin resistance gene, transferase
• Biological source: Escherichia coli
• Cellular location: Cell inner membrane ; Multi-pass membrane protein : A0A0R6L508
• Total number of polymer chains: 1
• Total formula weight: 37774.40

Authors

Wei, P.C.,Song, G.J.,Shi, M.Y.,Zhou, Y.F.,Liu, Y.,Lei, J.,Chen, P.,Yin, L. (deposition date: 2017-10-17, release date: 2017-11-08, Last modification date: 2024-10-23)

Primary citation

Wei, P.,Song, G.,Shi, M.,Zhou, Y.,Liu, Y.,Lei, J.,Chen, P.,Yin, L.
Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance.
FASEB J., 32:1085-1098, 2018

PubMed Abstract: Colistin is considered a last-resort antibiotic against most gram-negative bacteria. Recent discoveries of a plasmid-mediated, transferable mobilized colistin-resistance gene ( mcr-1) on all continents have heralded the imminent emergence of pan-drug-resistant superbacteria. The inner-membrane protein MCR-1 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in colistin resistance. However, little is known about the mechanism, and few drugs exist to address this issue. We present crystal structures revealing the MCR-1 catalytic domain (cMCR-1) as a monozinc metalloprotein with ethanolamine (ETA) and d-glucose, respectively, thus highlighting 2 possible substrate-binding pockets in the MCR-1-catalyzed PEA transfer reaction. Mutation of the residues involved in ETA and d-glucose binding impairs colistin resistance in recombinant Escherichia coli containing full-length MCR-1. Partial analogs of the substrate are used for cocrystallization with cMCR-1, providing valuable information about the family of PEA transferases. One of the analogs, ETA, causes clear inhibition of polymyxin B resistance, highlighting its potential for drug development. These data demonstrate the crucial role of the PEA- and lipid A-binding pockets and provide novel insights into the structure-based mechanisms, important drug-target hot spots, and a drug template for further drug development to combat the urgent, rising threat of MCR-1-mediated antibiotic resistance.-Wei, P., Song, G., Shi, M., Zhou, Y., Liu, Y., Lei, J., Chen, P., Yin, L. Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance.

PubMed: 29079699
DOI: 10.1096/fj.201700705R

Experimental method

X-RAY DIFFRACTION (1.5 Å)