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Helical Propensity in an Intrinsically Disordered Protein Accelerates Ligand Binding
Author(s) -
Iešmantavičius Vytautas,
Dogan Jakob,
Jemth Per,
Teilum Kaare,
Kjaergaard Magnus
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201307712
Subject(s) - intrinsically disordered proteins , chemistry , protein secondary structure , biophysics , coactivator , receptor–ligand kinetics , intermolecular force , crystallography , binding domain , kinetics , binding site , biochemistry , receptor , transcription factor , biology , molecule , organic chemistry , gene , physics , quantum mechanics
Many intrinsically disordered proteins fold upon binding to other macromolecules. The secondary structure present in the well‐ordered complex is often formed transiently in the unbound state. The consequence of such transient structure for the binding process is, however, not clear. The activation domain of the activator for thyroid hormone and retinoid receptors (ACTR) is intrinsically disordered and folds upon binding to the nuclear coactivator binding domain (NCBD) of the CREB binding protein. A number of mutants was designed that selectively perturbs the amount of secondary structure in unbound ACTR without interfering with the intermolecular interactions between ACTR and NCBD. Using NMR spectroscopy and fluorescence‐monitored stopped‐flow kinetic measurements we show that the secondary structure content in helix 1 of ACTR indeed influences the binding kinetics. The results thus support the notion of preformed secondary structure as an important determinant for molecular recognition in intrinsically disordered proteins.