Structural Biology Meets Drug Resistance: An Overview on Multidrug Resistance Transporters

Aqsa Shaheen, Mazhar Iqbal, Osman Mirza, Moazur Rahman


Structural biology provides snapshots of biological function
of molecular- and atomic-level structures of macromolecules, and
holds great promise in addressing the emerging problems of biomedical
science. Since the discovery of penicillin in early twentieth century,
mankind has become aware and confronted with the emergence of
antibiotic-resistant pathogens. In parallel to the failure of antibiotic therapy
against infectious pathogens, there had been continuous reports of
cancerous cells not responding to chemotherapy with increase in the
duration of therapy. Research on the underlying causes of multidrug
resistance in cancerous cells and later on in infectious bacteria revealed
the involvement of integral membrane transporters, capable of recognizing
a broad range of structurally different molecules as substrates and
exporting them from the cell using cellular energy. Structural biologists
succeeded in determining the structure of AcrB from Escherichia coli in
2002, the first structure of a multidrug resistance (MDR) transporter, and
since then rapid progress has been made in the structural elucidation
of these transporters. To date, structures of these transporters in apoand
substrate/inhibitor-bound state have been determined and deposited
in the protein databank. This repository is a valuable source for
structure-based drug design against MDR pumps. In this review, major
findings related to structural biology of MDR transporters belonging to
three major superfamilies, viz., ATP-binding cassette superfamily, major
facilitator superfamily and resistance nodulation division superfamily are
presented. Further, the future role of structural biology in improving our
understanding of drug–transporter interactions and in designing novel
inhibitors against MDR pump are discussed.

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