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Interactions of a bacterial RND transporter with a transmembrane small protein in a lipid environment

DOI: 10.1016/j.str.2020.03.013 DOI Help

Authors: Dijun Du (University of Cambridge) , Arthur Neuberger (University of Cambridge) , Mona Wu Orr (Eunice Kennedy Shriver National Institute of Child Health and Human Development) , Catherine E. Newman (University of Cambridge) , Pin-Chia Hsu (University of Southampton) , Firdaus Samsudin (University of Southampton) , Andrzej Szewczak-Harris (University of Cambridge) , Leana M. Ramos (Eunice Kennedy Shriver National Institute of Child Health and Human Development) , Mekdes Debela (University of Cambridge) , Syma Khalid (University of Southampton) , Gisela Storz (Eunice Kennedy Shriver National Institute of Child Health and Human Development) , Ben Luisi (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 28 , PAGES 625 - 634.e6

State: Published (Approved)
Published: June 2020

Open Access Open Access

Abstract: The small protein AcrZ in Escherichia coli interacts with the transmembrane portion of the multidrug efflux pump AcrB and increases resistance of the bacterium to a subset of the antibiotic substrates of that transporter. It is not clear how the physical association of the two proteins selectively changes activity of the pump for defined substrates. Here, we report cryo-EM structures of AcrB and the AcrBZ complex in lipid environments, and comparisons suggest that conformational changes occur in the drug-binding pocket as a result of AcrZ binding. Simulations indicate that cardiolipin preferentially interacts with the AcrBZ complex, due to increased contact surface, and we observe that chloramphenicol sensitivity of bacteria lacking AcrZ is exacerbated when combined with cardiolipin deficiency. Taken together, the data suggest that AcrZ and lipid cooperate to allosterically modulate AcrB activity. This mode of regulation by a small protein and lipid may occur for other membrane proteins.

Journal Keywords: drug efflux; small protein; antibiotic; transmembrane transport; structural model; cryoEM; molecular dynamics; allostery

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 07/01/2021 14:09

Documents:
1-s2.0-S0969212620300952-main.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Infectious Diseases Pathogens Structural biology

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)