ArticlePhysical chemistry chemical physics : PCCP2017
Rates and equilibrium constants of the ligand-induced conformational transition of an HCN ion channel protein domain determined by DEER spectroscopy.
Article in Physical chemistry chemical physics : PCCP, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 48 citations in OpenAlex.
- SOQS: Superposition of Quantum States for Selective Detection of Dipolar Frequency Multiples in Pulsed EPR Spectroscopy.ACS physical chemistry Au · 2026Article
- Protocol for preparing and characterizing samples for combined microsecond freeze-hyperquenching and electron paramagnetic resonance spectroscopy.STAR protocols · 2026Article
- A high-sensitivity stopped-flow EPR system to monitor millisecond conformational kinetics in spin-labeled proteins.Protein science : a publication of the Protein Society · 2025Article
- Quantification of Rapid Cooling of Glycerol/Water Solutions Based on Photoluminescence from Thioflavin T.The journal of physical chemistry. B · 2024Article
- Article
- Ligand-Coupled Conformational Changes in a Cyclic Nucleotide-Gated Ion Channel Revealed by Time-Resolved Transition Metal Ion FRET.bioRxiv : the preprint server for biology · 2024Article
- A high affinity switch for cAMP in the HCN pacemaker channels.Nature communications · 2024Article
- Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET.Nature communications · 2022Article
- Conformational Flexibility of the Protein Insertase BamA in the Native Asymmetric Bilayer Elucidated by ESR Spectroscopy.Angewandte Chemie (International ed. in English) · 2022Article
- Protein functional dynamics from the rigorous global analysis of DEER data: Conditions, components, and conformations.The Journal of general physiology · 2021Article
- Unraveling a Ligand-Induced Twist of a Homodimeric Enzyme by Pulsed Electron-Electron Double Resonance.Angewandte Chemie (International ed. in English) · 2021Article
- Article
- Methodology for rigorous modeling of protein conformational changes by Rosetta using DEER distance restraints.PLoS computational biology · 2021Article
- Viewing rare conformations of the βProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Characterization of the ExoU activation mechanism using EPR and integrative modeling.Scientific reports · 2020Article
- DeerLab: a comprehensive software package for analyzing dipolar electron paramagnetic resonance spectroscopy data.Magnetic resonance (Gottingen, Germany) · 2020Article
- Article
- Confidence Analysis of DEER Data and Its Structural Interpretation with Ensemble-Biased Metadynamics.Biophysical journal · 2018Article
- Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b.The Journal of biological chemistry · 2017Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
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Abstract
Ligand binding can induce significant conformational changes in proteins. The mechanism of this process couples equilibria associated with the ligand binding event and the conformational change. Here we show that by combining the application of W-band double electron-electron resonance (DEER) spectroscopy with microfluidic rapid freeze quench (μRFQ) it is possible to resolve these processes and obtain both equilibrium constants and reaction rates. We studied the conformational transition of the nitroxide labeled, isolated carboxy-terminal cyclic-nucleotide binding domain (CNBD) of the HCN2 ion channel upon binding of the ligand 3',5'-cyclic adenosine monophosphate (cAMP). Using model-based global analysis, the time-resolved data of the μRFQ DEER experiments directly provide fractional populations of the open and closed conformations as a function of time. We modeled the ligand-induced conformational change in the protein using a four-state model: apo/open (AO), apo/closed (AC), bound/open (BO), bound/closed (BC). These species interconvert according to AC + L ⇌ AO + L ⇌ BO ⇌ BC. By analyzing the concentration dependence of the relative contributions of the closed and open conformations at equilibrium, we estimated the equilibrium constants for the two conformational equilibria and the open-state ligand dissociation constant. Analysis of the time-resolved μRFQ DEER data gave estimates for the intrinsic rates of ligand binding and unbinding as well as the rates of the conformational change. This demonstrates that DEER can quantitatively resolve both the thermodynamics and the kinetics of ligand binding and the associated conformational change.
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