ArticlePLoS computational biology2012
Conformational control of the binding of the transactivation domain of the MLL protein and c-Myb to the KIX domain of CREB.
Article in PLoS computational biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Breaking the Myb-KIX Alliance: Structure-Guided Discovery of Biaryl Hydroxy-Naphthamides as Disruptors of the c-Myb-CBP/p300 KIX Protein-Protein Interaction.Archiv der Pharmazie · 2026Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Fluorine-Thiol Displacement Stapling on the Disordered αSynlett : accounts and rapid communications in synthetic organic chemistry · 2025Article
- Allostery in the dynamic coactivator domain KIX occurs through minor conformational micro-states.PLoS computational biology · 2022Article
- Revisiting allostery in CREB-binding protein (CBP) using residue-based interaction energy.Journal of computer-aided molecular design · 2020Article
- 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
- Expanding the Paradigm: Intrinsically Disordered Proteins and Allosteric Regulation.Journal of molecular biology · 2018Review
- Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell.Chemical reviews · 2016Review
- NMR Methods to Study Dynamic Allostery.PLoS computational biology · 2016Review
- Ethanol Activation of PKA Mediates Single-Minded 2 Expression in Neuronal Cells.Molecular neurobiology · 2015Article
- Adaptability of protein structures to enable functional interactions and evolutionary implications.Current opinion in structural biology · 2015Review
- Allosteric Dynamic Control of Binding.Biophysical journal · 2015Article
- Principles of allosteric interactions in cell signaling.Journal of the American Chemical Society · 2014Review
- The structural basis for cancer treatment decisions.Oncotarget · 2014Review
- Allostery within a transcription coactivator is predominantly mediated through dissociation rate constants.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Prepaying the entropic cost for allosteric regulation in KIX.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Dissecting allosteric effects of activator-coactivator complexes using a covalent small molecule ligand.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Multiple conformational selection and induced fit events take place in allosteric propagation.Biophysical chemistry · 2014Review
- Molecular recognition by the KIX domain and its role in gene regulation.Nucleic acids research · 2014Review
- Allosteric conformational barcodes direct signaling in the cell.Structure (London, England : 1993) · 2013Review
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3 authors.
Funding
Abstract
The KIX domain of CBP is a transcriptional coactivator. Concomitant binding to the activation domain of proto-oncogene protein c-Myb and the transactivation domain of the trithorax group protein mixed lineage leukemia (MLL) transcription factor lead to the biologically active ternary MLL∶KIX∶c-Myb complex which plays a role in Pol II-mediated transcription. The binding of the activation domain of MLL to KIX enhances c-Myb binding. Here we carried out molecular dynamics (MD) simulations for the MLL∶KIX∶c-Myb ternary complex, its binary components and KIX with the goal of providing a mechanistic explanation for the experimental observations. The dynamic behavior revealed that the MLL binding site is allosterically coupled to the c-Myb binding site. MLL binding redistributes the conformational ensemble of KIX, leading to higher populations of states which favor c-Myb binding. The key element in the allosteric communication pathways is the KIX loop, which acts as a control mechanism to enhance subsequent binding events. We tested this conclusion by in silico mutations of loop residues in the KIX∶MLL complex and by comparing wild type and mutant dynamics through MD simulations. The loop assumed MLL binding conformation similar to that observed in the KIX∶c-Myb state which disfavors the allosteric network. The coupling with c-Myb binding site faded, abolishing the positive cooperativity observed in the presence of MLL. Our major conclusion is that by eliciting a loop-mediated allosteric switch between the different states following the binding events, transcriptional activation can be regulated. The KIX system presents an example how nature makes use of conformational control in higher level regulation of transcriptional activity and thus cellular events.
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