Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

Research output: Contribution to journalArticle

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Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin. / Olatunji, Samir; Yu, Xiaoxiao; Bailey, Jonathan; Huang, Chia-Ying; Zapotoczna, Marta; Bowen, Katherine; Remškar, Maja; Müller, Rolf; Scanlan, Eoin M; Geoghegan, Joan A; Olieric, Vincent; Caffrey, Martin.

In: Nature Communications, Vol. 11, No. 1, 140, 09.01.2020.

Research output: Contribution to journalArticle

Harvard

Olatunji, S, Yu, X, Bailey, J, Huang, C-Y, Zapotoczna, M, Bowen, K, Remškar, M, Müller, R, Scanlan, EM, Geoghegan, JA, Olieric, V & Caffrey, M 2020, 'Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin', Nature Communications, vol. 11, no. 1, 140. https://doi.org/10.1038/s41467-019-13724-y

APA

Olatunji, S., Yu, X., Bailey, J., Huang, C-Y., Zapotoczna, M., Bowen, K., Remškar, M., Müller, R., Scanlan, E. M., Geoghegan, J. A., Olieric, V., & Caffrey, M. (2020). Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin. Nature Communications, 11(1), [140]. https://doi.org/10.1038/s41467-019-13724-y

Vancouver

Author

Olatunji, Samir ; Yu, Xiaoxiao ; Bailey, Jonathan ; Huang, Chia-Ying ; Zapotoczna, Marta ; Bowen, Katherine ; Remškar, Maja ; Müller, Rolf ; Scanlan, Eoin M ; Geoghegan, Joan A ; Olieric, Vincent ; Caffrey, Martin. / Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin. In: Nature Communications. 2020 ; Vol. 11, No. 1.

Bibtex

@article{2229bcd84d1c41818ffd5fed0bcb5540,
title = "Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin",
abstract = "Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.",
keywords = "Aspartic Acid Endopeptidases/metabolism, Bacterial Proteins/metabolism, Binding Sites/physiology, Cell Membrane/drug effects, Crystallography, X-Ray, Drug Resistance, Bacterial/genetics, Macrolides/metabolism, Methicillin-Resistant Staphylococcus aureus/enzymology, Peptides/metabolism, Protein Binding/physiology, Protein Structure, Tertiary",
author = "Samir Olatunji and Xiaoxiao Yu and Jonathan Bailey and Chia-Ying Huang and Marta Zapotoczna and Katherine Bowen and Maja Rem{\v s}kar and Rolf M{\"u}ller and Scanlan, {Eoin M} and Geoghegan, {Joan A} and Vincent Olieric and Martin Caffrey",
year = "2020",
month = jan,
day = "9",
doi = "10.1038/s41467-019-13724-y",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

T1 - Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin

AU - Olatunji, Samir

AU - Yu, Xiaoxiao

AU - Bailey, Jonathan

AU - Huang, Chia-Ying

AU - Zapotoczna, Marta

AU - Bowen, Katherine

AU - Remškar, Maja

AU - Müller, Rolf

AU - Scanlan, Eoin M

AU - Geoghegan, Joan A

AU - Olieric, Vincent

AU - Caffrey, Martin

PY - 2020/1/9

Y1 - 2020/1/9

N2 - Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.

AB - Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.

KW - Aspartic Acid Endopeptidases/metabolism

KW - Bacterial Proteins/metabolism

KW - Binding Sites/physiology

KW - Cell Membrane/drug effects

KW - Crystallography, X-Ray

KW - Drug Resistance, Bacterial/genetics

KW - Macrolides/metabolism

KW - Methicillin-Resistant Staphylococcus aureus/enzymology

KW - Peptides/metabolism

KW - Protein Binding/physiology

KW - Protein Structure, Tertiary

UR - http://www.scopus.com/inward/record.url?scp=85077693849&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-13724-y

DO - 10.1038/s41467-019-13724-y

M3 - Article

C2 - 31919415

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 140

ER -