Microbiology news and views
J. Mol. Micro. Biotechnol. 3: 151-154
The Ostensible Paradox of Multidrug Recognition
Alex A. Neyfakh
The ability of multidrug-efflux transporters to recognize scores of dissimilar organic compounds has
always been considered paradoxical because of its apparent contradiction to some of the basic dogmas of
biochemistry. In order to understand, at least in principle, how a protein can recognize multiple compounds, we analysed
the transcriptional regulator of the Bacillus
subtilis multidrug transporter Bmr. This regulator, BmrR, binds
multiple dissimilar hydrophobic cations and, by activating expression of the Bmr transporter, causes their
expulsion from the cell. Crystallographic analysis of the complexes of the inducer-binding domain of BmrR with some
of its inducers revealed that ligands penetrate the hydrophobic core of the protein, where they form multiple
van der Waals and stacking interactions with hydrophobic amino acids and an electrostatic bond with the
buried glutamate. Mutational analysis of the binding site suggests that each ligand forms a unique set of
atomic contacts with the protein: each tested mutation exerted disparate effects on the binding of different
ligands. The example of BmrR demonstrates that a protein can bind multiple hydrophobic compounds with
micromolar affinities by using only electrostatic and hydrophobic interactions. Its ligand specificity can be further
broadened by the flexibility of the binding site. It appears, therefore, that the commonly expressed fascination with
the relaxed substrate specificity of multidrug transporters is misdirected and originates from an almost
exclusive familiarity with the more sophisticated processes of specific molecular recognition that predominate
among proteins analyzed to date.
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