Entropy redistribution controls allostery in a metalloregulatory protein

DAIANA ANDREA CAPDEVILA; JOSEPH BRAYMER; KATHERINE EDMONDS; HONGWEI WU; DAVID GIEDROC

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2017

0027-8424

Allosteric communication between two ligand-binding sites in a protein is a central aspect of biological regulation, but remains mechanistically unclear. Here we show that perturbations in equilibrium picosecond-nanosecond motions drive zinc (Zn)-induced allosteric inhibition of DNA binding by the Zn efflux repressor CzrA. DNA binding leads to an unanticipated increase in methyl side-chain flexibility and thus is stabilized by a substantial favorable entropic driving force; 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 non-native 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. This work illustrates of how driving forces arising from dynamics can be harnessed by nature to evolve new allosteric ligand specificities in a compact molecular scaffold.