Structure snapshots reveal the mechanism of a bacterial membrane lipoprotein N -acyltransferase

Author:

Smithers Luke1ORCID,Degtjarik Oksana2ORCID,Weichert Dietmar1ORCID,Huang Chia-Ying3ORCID,Boland Coilín1ORCID,Bowen Katherine4ORCID,Oluwole Abraham5ORCID,Lutomski Corinne5ORCID,Robinson Carol V.5ORCID,Scanlan Eoin M.4ORCID,Wang Meitian3ORCID,Olieric Vincent3ORCID,Shalev-Benami Moran2ORCID,Caffrey Martin1ORCID

Affiliation:

1. School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, Dublin D02 R590, Ireland.

2. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.

3. Swiss Light Source, Paul Scherrer Institute, CH-5232 Villigen, Switzerland.

4. School of Chemistry, Trinity College Dublin, Dublin D02 R590, Ireland.

5. Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

Abstract

Bacterial lipoproteins (BLPs) decorate the surface of membranes in the cell envelope. They function in membrane assembly and stability, as enzymes, and in transport. The final enzyme in the BLP synthesis pathway is the apolipoprotein N -acyltransferase, Lnt, which is proposed to act by a ping-pong mechanism. Here, we use x-ray crystallography and cryo–electron microscopy to chart the structural changes undergone during the progress of the enzyme through the reaction. We identify a single active site that has evolved to bind, individually and sequentially, substrates that satisfy structural and chemical criteria to position reactive parts next to the catalytic triad for reaction. This study validates the ping-pong mechanism, explains the molecular bases for Lnt’s substrate promiscuity, and should facilitate the design of antibiotics with minimal off-target effects.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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