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

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Ratnaweera, Malitha  ORCID logo
Luisi, Ben F 
Ntsogo Enguéné, Véronique Yvette  ORCID logo


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.



allostery, antimicrobial resistance, conformational changes, efflux pump, energetic transition, gram-negative bacteria, pump activation

Journal Title

Antibiotics (Basel)

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European Research Council (742210)
Wellcome Trust (200873/Z/16/Z)