SITE SPECIFIC DYNAMICS MODULATE ALLOSTERY

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

Lousville

Congreso; 2016 NMR gateway; 2016

Gateway NMR organizing committee

We propose a model of allostery in a compact, single domain metalloregulatory protein that can be entirely explained by a redistribution of site-specific conformational entropy. We use a well-developed model system, a zinc (Zn)-sensing transcriptional repressor from the Staphylococcus aureus, to provide unprecedented insights into heterotropic allostery, the inhibition of DNA operator binding by the allosteric ligand Zn. By employing methyl groups as reporters of conformational entropy, we show that Zn binding renders inaccessible a highly dynamic DNA-bound conformation. We further show for the first time, that these entropic fingerprints pinpoint ?hot spots? that when mutated, specifically impair allosteric coupling of Zn and DNA binding. Finally, we show that these hot spots define a limited number of sites that nature has exploited to evolve and expand the extraordinary functional diversity of this family of bacterial repressors. We postulate that our findings are representative of many compact proteins where a redistribution of dynamical disorder is used to drive biological regulation.