5uxc

Crystal structure of macrolide 2'-phosphotransferase MphH from Brachybacterium faecium in complex with GDP

spinqualitylabelsall models 5uxc, resolution 1.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5uxc is a 1 chain structure with sequence from Brachybacterium faecium DSM 4810. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.72Å Ligands: CL, GDP, GOL, MG, MSE, PGE, PO4, SO4, ZIT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C7MEP1_BRAFD Publication Abstract from PubMed The production of antibiotics by microbes in the environment and their use in medicine and agriculture select for existing and emerging resistance. To address this inevitability, prudent development of antibiotic drugs requires careful consideration of resistance evolution. Here, we identify the molecular basis for expanded substrate specificity in MphI, a macrolide kinase (Mph) that does not confer resistance to erythromycin, in contrast to other known Mphs. Using a combination of phylogenetics, drug-resistance phenotypes, and in vitro enzyme assays, we find that MphI and MphK phosphorylate erythromycin poorly resulting in an antibiotic-sensitive phenotype. Using likelihood reconstruction of ancestral sequences and site-saturation combinatorial mutagenesis, supported by Mph crystal structures, we determine that two non-obvious mutations in combination expand the substrate range. This approach should be applicable for studying the functional evolution of any antibiotic resistance enzyme and for evaluating the evolvability of resistance enzymes to new generations of antibiotic scaffolds. The evolution of substrate discrimination in macrolide antibiotic resistance enzymes.,Pawlowski AC, Stogios PJ, Koteva K, Skarina T, Evdokimova E, Savchenko A, Wright GD Nat Commun. 2018 Jan 9;9(1):112. doi: 10.1038/s41467-017-02680-0. PMID:29317655 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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