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Towards an Understanding of Ligand Induced Functional Conformational Changes of MexB Efflux Transporter

preprint
submitted on 06.03.2021, 21:39 and posted on 10.03.2021, 12:14 by Khondaker Miraz Rahman, Shirin Jamshidi, J Mark Sutton, Sara Jambarsang

MexB, an RND-superfamily efflux pump, plays a vital role in conferring resistance to cytotoxic molecules, including antibiotics, upon Gram-negative bacteria. Although the principal mechanistic elements of switching between the access, binding and extrusion conformers of the protomers of tripartite efflux transporters have been described previously, details surrounding the further mechanism that ends in either substrate extrusion or pump inhibition are limited to observations based on the type of ligand bound to the transporter. A central but missing link in the structure/mechanism relationship is a description of how ligand-induced conformational changes in the presence of a membrane and changing transporter protonation state lead to either substrate extrusion or inhibition of the pump. Here, we report that differences in conformational changes are governed by ligand binding to the transporter. The current study describes important new information about ligand-induced structural rearrangements and conformational changes of MexB in relation to the protonation state of critical acidic residues. We used tetracycline (TET) as a model substrate of MexB and phenylalanine-arginine beta-naphthylamide (PAβN) as a model inhibitor of MexB to study the aforementioned conformational changes. This new information will contribute to the design of new, effective and selective efflux pump inhibitors that could play key roles in reversing antimicrobial resistance.

Funding

NBIC, BBSRC

History

Email Address of Submitting Author

k.miraz.rahman@kcl.ac.uk

Institution

King's College London

Country

United Kingdom

ORCID For Submitting Author

0000-0001-8566-8648

Declaration of Conflict of Interest

No conflict of interest

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