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Structure of a lipid A phosphoethanolamine transferase suggests how conformational changes govern substrate binding

2017; National Academy of Sciences; Volume: 114; Issue: 9 Linguagem: Inglês

10.1073/pnas.1612927114

1091-6490

Anandhi Anandan, Genevieve L. Evans, Karmen Čondić‐Jurkić, Megan L. O’Mara, Constance M. John, Nancy J. Phillips, Gary A. Jarvis, Siobhán Wills, Keith A. Stubbs, Isabel Moraes, Charlene M. Kahler, Alice Vrielink,

RNA and protein synthesis mechanisms

Significance At this time, multidrug-resistant gram-negative bacteria are estimated to cause approximately 700,000 deaths per year globally, with a prediction that this figure could reach 10 million a year by 2050. Antivirulence therapy, in which virulence mechanisms of a pathogen are chemically inactivated, represents a promising approach to the development of treatment options. The family of lipid A phosphoethanolamine transferases in gram-negative bacteria confers bacterial resistance to innate immune defensins and colistin antibiotics. The development of inhibitors to block lipid A phosphoethanolamine transferase could improve innate immune clearance and extend the usefulness of colistin antibiotics. The solved crystal structure and biophysical studies suggest that the enzyme undergoes large conformational changes to enable binding and catalysis of two very differently sized substrates.