ArticleProceedings of the National Academy of Sciences of the United States of America2015
Conformational kinetics reveals affinities of protein conformational states.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Molecular basis for cold and menthol sensing by mammalian TRPM8.Nature communications · 2026Article
- Exploring the interplay between protein conformational changes and phosphorylation in a pancreatic cancer cell and stellate cell coculture system.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.Nature communications · 2025Article
- Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.Research square · 2024Article
- Ligand-induced protein transition state stabilization switches the binding pathway from conformational selection to induced fit.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Elucidating the mechanisms underlying protein conformational switching using NMR spectroscopy.Journal of magnetic resonance open · 2022Article
- Unveiling the "invisible" druggable conformations of GDP-bound inactive Ras.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Mechanisms of ligand binding.Biophysics reviews · 2020Review
- Exposing Hidden High-Affinity RNA Conformational States.Journal of the American Chemical Society · 2020Article
- A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding.Protein science : a publication of the Protein Society · 2019Review
- Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-Journal of medicinal chemistry · 2019Article
- Is TCR/pMHC Affinity a Good Estimate of the T-cell Response? An Answer Based on Predictions From 12 Phenotypic Models.Frontiers in immunology · 2019Article
- Exploring the structural origins of cryptic sites on proteins.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Unified understanding of folding and binding mechanisms of globular and intrinsically disordered proteins.Biophysical reviews · 2018Review
- Article
- Rate Constants and Mechanisms of Protein-Ligand Binding.Annual review of biophysics · 2017Review
- Article
- How to Distinguish Conformational Selection and Induced Fit Based on Chemical Relaxation Rates.PLoS computational biology · 2016Article
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Authors and funding
3 authors.
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Abstract
Most biological reactions rely on interplay between binding and changes in both macromolecular structure and dynamics. Practical understanding of this interplay requires detection of critical intermediates and determination of their binding and conformational characteristics. However, many of these species are only transiently present and they have often been overlooked in mechanistic studies of reactions that couple binding to conformational change. We monitored the kinetics of ligand-induced conformational changes in a small protein using six different ligands. We analyzed the kinetic data to simultaneously determine both binding affinities for the conformational states and the rate constants of conformational change. The approach we used is sufficiently robust to determine the affinities of three conformational states and detect even modest differences in the protein's affinities for relatively similar ligands. Ligand binding favors higher-affinity conformational states by increasing forward conformational rate constants and/or decreasing reverse conformational rate constants. The amounts by which forward rate constants increase and reverse rate constants decrease are proportional to the ratio of affinities of the conformational states. We also show that both the affinity ratio and another parameter, which quantifies the changes in conformational rate constants upon ligand binding, are strong determinants of the mechanism (conformational selection and/or induced fit) of molecular recognition. Our results highlight the utility of analyzing the kinetics of conformational changes to determine affinities that cannot be determined from equilibrium experiments. Most importantly, they demonstrate an inextricable link between conformational dynamics and the binding affinities of conformational states.
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