5IGT

Macrolide 2'-phosphotransferase type I - complex with guanosine and erythromycin

Summary for 5IGT

• Entry DOI: 10.2210/pdb5igt/pdb
• Related: 5IGH 5IGI 5IGJ 5IGP 5IGR 5IGS 5IGU 5IGV 5IGW 5IGY 5IGZ 5IH0 5IH1
• Descriptor: Macrolide 2'-phosphotransferase, GUANOSINE, ERYTHROMYCIN A, ... (5 entities in total)
• Functional Keywords: macrolide phosphotransferase, kinase, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 34406.14

Authors

Berghuis, A.M.,Fong, D.H. (deposition date: 2016-02-28, release date: 2017-04-26, Last modification date: 2023-09-27)

Primary citation

Fong, D.H.,Burk, D.L.,Blanchet, J.,Yan, A.Y.,Berghuis, A.M.
Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance.
Structure, 25:750-761.e5, 2017

PubMed Abstract: The macrolides are a class of antibiotic, characterized by a large macrocyclic lactone ring that can be inactivated by macrolide phosphotransferase enzymes. We present structures for MPH(2')-I and MPH(2')-II in the apo state, and in complex with GTP analogs and six different macrolides. These represent the first structures from the two main classes of macrolide phosphotransferases. The structures show that the enzymes are related to the aminoglycoside phosphotransferases, but are distinguished from them by the presence of a large interdomain linker that contributes to an expanded antibiotic binding pocket. This pocket is largely hydrophobic, with a negatively charged patch located at a conserved aspartate residue, rationalizing the broad-spectrum resistance conferred by the enzymes. Complementary mutation studies provide insights into factors governing substrate specificity. A comparison with macrolides bound to their natural target, the 50S ribosome, suggests avenues for next-generation antibiotic development.

PubMed: 28416110
DOI: 10.1016/j.str.2017.03.007

Experimental method

X-RAY DIFFRACTION (1.39 Å)