The ostensible paradox of multidrug recognition

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Multidrug-efflux transporters recognize numerous dissimilar organic compounds, a paradox in biochemistry.
• Understanding this relaxed substrate specificity is crucial for drug development and combating resistance.

Purpose of the Study:

• To elucidate the molecular mechanism by which a protein can recognize and bind multiple dissimilar compounds.
• To analyze the transcriptional regulator BmrR from Bacillus subtilis, which controls the Bmr multidrug transporter.

Main Methods:

• Crystallographic analysis of the inducer-binding domain of BmrR with its ligands.
• Mutational analysis of the BmrR binding site to assess ligand interactions.

Main Results:

• BmrR's inducer-binding domain binds multiple hydrophobic cations via van der Waals, stacking, and electrostatic interactions with a buried glutamate.
• Ligand binding involves unique atomic contacts for each inducer, with mutations affecting different ligands disparately.
• BmrR demonstrates that proteins can bind multiple hydrophobic compounds with micromolar affinity using only hydrophobic and electrostatic forces.

Conclusions:

• The flexibility of the binding site broadens ligand specificity in proteins like BmrR.
• The apparent paradox of multidrug transporter recognition is explained by flexible binding sites and non-specific interactions.
• This study reframes the understanding of substrate specificity in multidrug transporters.