The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity

David N. Bolam; Shirley Roberts; Mark R. Proctor; Johan P. Turkenburg; Eleanor J. Dodson; Carlos Martinez-Fleites; Min Yang; Benjamin G. Davis; Gideon J. Davies; Harry J. Gilbert

doi:10.1073/pnas.0607897104

The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity

David N. Bolam, Shirley Roberts, Mark R. Proctor, Johan P. Turkenburg, Eleanor J. Dodson, Carlos Martinez-Fleites, Min Yang, Benjamin G. Davis, Gideon J. Davies, Harry J. Gilbert

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, Olel and OIeD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme-ligand complexes, in tandem with kinetic analysis of site-directed variants, provide insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OIeD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin, when bound to OIeD and Olel, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. The data reported here provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling.

Original language	English
Pages (from-to)	5336-5341
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	104
Issue number	13
DOIs	https://doi.org/10.1073/pnas.0607897104
Publication status	Published - 27 Mar 2007

Keywords

enzymology
glycobiology
erythromycin
streptomyces
glycoside
STREPTOMYCES-ANTIBIOTICUS
BIOSYNTHETIC-PATHWAY
OLEANDOMYCIN
GLUCOSYLTRANSFERASE
GLYCOSYLATION
SYNTHASE
REVEALS
PURIFICATION
REFINEMENT
RESISTANCE

Access to Document

10.1073/pnas.0607897104

Cite this

Bolam, D. N., Roberts, S., Proctor, M. R., Turkenburg, J. P., Dodson, E. J., Martinez-Fleites, C., Yang, M., Davis, B. G., Davies, G. J., & Gilbert, H. J. (2007). The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity. Proceedings of the National Academy of Sciences of the United States of America, 104(13), 5336-5341. https://doi.org/10.1073/pnas.0607897104

@article{75fc31da653b47f795d0da6a6cebe077,

title = "The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity",

abstract = "Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, Olel and OIeD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme-ligand complexes, in tandem with kinetic analysis of site-directed variants, provide insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OIeD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin, when bound to OIeD and Olel, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. The data reported here provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling.",

keywords = "enzymology, glycobiology, erythromycin, streptomyces, glycoside, STREPTOMYCES-ANTIBIOTICUS, BIOSYNTHETIC-PATHWAY, OLEANDOMYCIN, GLUCOSYLTRANSFERASE, GLYCOSYLATION, SYNTHASE, REVEALS, PURIFICATION, REFINEMENT, RESISTANCE",

author = "Bolam, {David N.} and Shirley Roberts and Proctor, {Mark R.} and Turkenburg, {Johan P.} and Dodson, {Eleanor J.} and Carlos Martinez-Fleites and Min Yang and Davis, {Benjamin G.} and Davies, {Gideon J.} and Gilbert, {Harry J.}",

year = "2007",

month = mar,

day = "27",

doi = "10.1073/pnas.0607897104",

language = "English",

volume = "104",

pages = "5336--5341",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "13",

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Bolam, DN, Roberts, S, Proctor, MR, Turkenburg, JP, Dodson, EJ, Martinez-Fleites, C, Yang, M, Davis, BG, Davies, GJ & Gilbert, HJ 2007, 'The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 13, pp. 5336-5341. https://doi.org/10.1073/pnas.0607897104

The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity. / Bolam, David N.; Roberts, Shirley; Proctor, Mark R. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 13, 27.03.2007, p. 5336-5341.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity

AU - Bolam, David N.

AU - Roberts, Shirley

AU - Proctor, Mark R.

AU - Turkenburg, Johan P.

AU - Dodson, Eleanor J.

AU - Martinez-Fleites, Carlos

AU - Yang, Min

AU - Davis, Benjamin G.

AU - Davies, Gideon J.

AU - Gilbert, Harry J.

PY - 2007/3/27

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N2 - Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, Olel and OIeD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme-ligand complexes, in tandem with kinetic analysis of site-directed variants, provide insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OIeD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin, when bound to OIeD and Olel, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. The data reported here provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling.

AB - Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, Olel and OIeD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme-ligand complexes, in tandem with kinetic analysis of site-directed variants, provide insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OIeD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin, when bound to OIeD and Olel, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. The data reported here provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling.

KW - enzymology

KW - glycobiology

KW - erythromycin

KW - streptomyces

KW - glycoside

KW - STREPTOMYCES-ANTIBIOTICUS

KW - BIOSYNTHETIC-PATHWAY

KW - OLEANDOMYCIN

KW - GLUCOSYLTRANSFERASE

KW - GLYCOSYLATION

KW - SYNTHASE

KW - REVEALS

KW - PURIFICATION

KW - REFINEMENT

KW - RESISTANCE

U2 - 10.1073/pnas.0607897104

DO - 10.1073/pnas.0607897104

M3 - Article

SN - 0027-8424

VL - 104

SP - 5336

EP - 5341

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 13

ER -