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Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4424-4429. doi: 10.1073/pnas.1620665114. Epub 2017 Mar 27.

Entropy redistribution controls allostery in a metalloregulatory protein.

Author information

1
Department of Chemistry, Indiana University, Bloomington, IN 47405.
2
Department of Chemistry, Indiana University, Bloomington, IN 47405 giedroc@indiana.edu.

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.

KEYWORDS:

allostery; conformational entropy; protein dynamics; transcription factors; zinc homeostasis

Comment in

PMID:
28348247
PMCID:
PMC5410788
DOI:
10.1073/pnas.1620665114
[Indexed for MEDLINE]
Free PMC Article

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