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J Mol Biol. 2015 Apr 24;427(8):1695-704. doi: 10.1016/j.jmb.2015.02.021. Epub 2015 Mar 4.

Allosteric coupling via distant disorder-to-order transitions.

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Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. Electronic address:


Intrinsic disorder provides a means of maximizing allosteric coupling in proteins. However, the mechanisms by which the disorder functions in allostery remain to be elucidated. Small ligand, bio-5'-AMP, binding and dimerization of the Escherichia coli biotin repressor are allosterically coupled. Folding of a disordered loop in the allosteric effector binding site is required to realize the full coupling free energy of -4.0 ± 0.3 kcal/mol observed in the wild-type protein. Alanine substitution of a glycine residue on the dimerization surface that does not directly contribute to the dimerization interface completely abolishes this coupling. In this work, the structure of this variant, solved by X-ray crystallography, reveals a monomeric corepressor-bound protein. In the structure loops, neither of which contains the alanine substitution, on both the dimerization and effector binding surfaces that are folded in the corepressor-bound wild-type protein are disordered. The structural data combined with functional measurements indicate that allosteric coupling between ligand binding and dimerization in BirA (E. coli biotin repressor/biotin protein ligase) is achieved via reciprocal communication of disorder-to-order transitions on two distant functional surfaces.


allostery; coupled equilibria; disorder-to-order; protein:ligand interactions; protein:protein interactions

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