title: Entropy redistribution controls allostery in a metalloregulatory protein.
abstract: Allosteric communication between two ligand-binding sites in a protein is a central aspect of biological regulation that remains mechanistically unclear. Here we show that perturbations in equilibrium picosecond-nanosecond motions impact zinc (Zn)-induced allosteric inhibition of DNA binding by the Zn efflux repressor CzrA (chromosomal zinc-regulated repressor). DNA binding leads to an unanticipated increase in methyl side-chain flexibility and thus stabilizes the complex entropically; Zn binding redistributes these motions, inhibiting formation of the DNA complex by restricting coupled fast motions and concerted slower motions. Allosterically impaired CzrA mutants are characterized by distinct nonnative fast internal dynamics "fingerprints" upon Zn binding, and DNA binding is weakly regulated. We demonstrate the predictive power of the wild-type dynamics fingerprint to identify key residues in dynamics-driven allostery. We propose that driving forces arising from dynamics can be harnessed by nature to evolve new allosteric ligand specificities in a compact molecular scaffold.
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405.
authors.forename: Daiana A
authors.initials: DA
authors.lastname: Capdevila
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Braymer
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Edmonds
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405 giedroc@indiana.edu.
authors.forename: David P
authors.initials: DP
authors.lastname: Giedroc
mesh_terms: D000494:Allosteric Regulation; D001426:Bacterial Proteins / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D019277:Entropy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000378:metabolism; D013696:Temperature; D015032:Zinc / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C120278:CzrA protein, Staphylococcus aureus; D004268:DNA-Binding Proteins; D015032:Zinc
keywords: allostery; conformational entropy; protein dynamics; transcription factors; zinc homeostasis