A Model for Allosteric Communication in Drug Transport by the AcrAB-TolC Tripartite Efflux Pump

Antibiotics

Anya Webber¹  Ben F. Luisi¹  Andrzej Harris¹  Véronique Yvette Ntsogo Enguéné¹  Malitha Ratnaweera² 

[1] Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK;Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK;

关键词: allostery;    antimicrobial resistance;    conformational changes;    efflux pump;    energetic transition;    gram-negative bacteria;   

DOI  :  10.3390/antibiotics11010052

来源: DOAJ

【 摘 要 】

RND family efflux pumps are complex macromolecular machines involved in multidrug resistance by extruding antibiotics from the cell. While structural studies and molecular dynamics simulations have provided insights into the architecture and conformational states of the pumps, the path followed by conformational changes from the inner membrane protein (IMP) to the periplasmic membrane fusion protein (MFP) and to the outer membrane protein (OMP) in tripartite efflux assemblies is not fully understood. Here, we investigated AcrAB-TolC efflux pump’s allostery by comparing resting and transport states using difference distance matrices supplemented with evolutionary couplings data and buried surface area measurements. Our analysis indicated that substrate binding by the IMP triggers quaternary level conformational changes in the MFP, which induce OMP to switch from the closed state to the open state, accompanied by a considerable increase in the interface area between the MFP subunits and between the OMPs and MFPs. This suggests that the pump’s transport-ready state is at a more favourable energy level than the resting state, but raises the puzzle of how the pump does not become stably trapped in a transport-intermediate state. We propose a model for pump allostery that includes a downhill energetic transition process from a proposed ‘activated’ transport state back to the resting pump.

【 授权许可】

Unknown