ArticleProceedings of the National Academy of Sciences of the United States of America2014
Prepaying the entropic cost for allosteric regulation in KIX.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 53 citations in OpenAlex.
- Recognition of the CREB-Binding Protein/Mixed Lineage Leukemia Interface by Sulfonyl-γ-AApeptides: Beyond Mimicry of Mixed Lineage Leukemia.Journal of medicinal chemistry · 2025Article
- Allostery in the dynamic coactivator domain KIX occurs through minor conformational micro-states.PLoS computational biology · 2022Article
- Molecular Simulations of Intrinsically Disordered Proteins and Their Binding Mechanisms.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions.Biomolecules · 2021Review
- Intrinsic Disorder in Plant Transcription Factor Systems: Functional Implications.International journal of molecular sciences · 2020Review
- Revisiting allostery in CREB-binding protein (CBP) using residue-based interaction energy.Journal of computer-aided molecular design · 2020Article
- Globally correlated conformational entropy underlies positive and negative cooperativity in a kinase's enzymatic cycle.Nature communications · 2019Article
- Residual Structure Accelerates Binding of Intrinsically Disordered ACTR by Promoting Efficient Folding upon Encounter.Journal of molecular biology · 2019Article
- Structural basis for cooperative regulation of KIX-mediated transcription pathways by the HTLV-1 HBZ activation domain.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Expanding the Paradigm: Intrinsically Disordered Proteins and Allosteric Regulation.Journal of molecular biology · 2018Review
- Modulating the masters: chemical tools to dissect CBP and p300 function.Current opinion in chemical biology · 2018Review
- Investigation of sliding DNA clamp dynamics by single-molecule fluorescence, mass spectrometry and structure-based modeling.Nucleic acids research · 2018Article
- Phosphorylation of the IDP KID Modulates Affinity for KIX by Increasing the Lifetime of the Complex.Biophysical journal · 2017Article
- KIXBASE: A comprehensive web resource for identification and exploration of KIX domains.Scientific reports · 2017Article
- Role of non-native electrostatic interactions in the coupled folding and binding of PUMA with Mcl-1.PLoS computational biology · 2017Article
- From Fuzzy to Function: The New Frontier of Protein-Protein Interactions.Accounts of chemical research · 2017Article
- Disorder drives cooperative folding in a multidomain protein.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Dynamics of the Extended String-Like Interaction of TFIIE with the p62 Subunit of TFIIH.Biophysical journal · 2016Article
- Capturing a Dynamic Chaperone-Substrate Interaction Using NMR-Informed Molecular Modeling.Journal of the American Chemical Society · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The kinase-inducible domain interacting (KIX) domain of the CREB binding protein (CBP) is capable of simultaneously binding two intrinsically disordered transcription factors, such as the mixed-lineage leukemia (MLL) and c-Myb peptides, at isolated interaction sites. In vitro, the affinity for binding c-Myb is approximately doubled when KIX is in complex with MLL, which suggests a positive cooperative binding mechanism, and the affinity for MLL is also slightly increased when KIX is first bound by c-Myb. Expanding the scope of recent NMR and computational studies, we explore the allosteric mechanism at a detailed molecular level that directly connects the microscopic structural dynamics to the macroscopic shift in binding affinities. To this end, we have performed molecular dynamics simulations of free KIX, KIX-c-Myb, MLL-KIX, and MLL-KIX-c-Myb using a topology-based Gō-like model. Our results capture an increase in affinity for the peptide in the allosteric site when KIX is prebound by a complementary effector and both peptides follow an effector-independent folding-and-binding mechanism. More importantly, we discover that MLL binding lowers the entropic cost for c-Myb binding, and vice versa, by stabilizing the L12-G2 loop and the C-terminal region of the α3 helix on KIX. This work demonstrates the importance of entropy in allosteric signaling between promiscuous molecular recognition sites and can inform the rational design of small molecule stabilizers to target important regions of conformationally dynamic proteins.
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