ArticleACS chemical biology2013
Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule.
Article in ACS chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- Minimal Collective Variables for Conformational Transitions in Steered and Temperature-Accelerated MD Simulations: A T4 Lysozyme Case Study.The journal of physical chemistry. B · 2025Article
- Coupling of conformational dynamics and inhibitor binding in the phosphodiesterase-5 family.Protein science : a publication of the Protein Society · 2023Article
- Identification of core allosteric sites through temperature- and nucleus-invariant chemical shift covariance.Biophysical journal · 2022Article
- Mixed-solvent molecular dynamics simulation-based discovery of a putative allosteric site on regulator of G protein signaling 4.Journal of computational chemistry · 2021Article
- Allosteric Pathways Originating at Cysteine Residues in Regulators of G-Protein Signaling Proteins.Biophysical journal · 2021Article
- Engineering and application of a biosensor with focused ligand specificity.Nature communications · 2020Article
- Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials.The Journal of biological chemistry · 2019Review
- Structural Analysis and Dynamic Processes of the Transmembrane Segment Inside Different Micellar Environments-Implications for the TM4 Fragment of the Bilitranslocase Protein.International journal of molecular sciences · 2019Article
- Interplay of cysteine exposure and global protein dynamics in small-molecule recognition by a regulator of G-protein signaling protein.Proteins · 2019Article
- Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures.SLAS discovery : advancing life sciences R & D · 2018Article
- Differential Protein Dynamics of Regulators of G-Protein Signaling: Role in Specificity of Small-Molecule Inhibitors.Journal of the American Chemical Society · 2018Article
- Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines.Journal of natural products · 2017Article
- Development of a bimolecular luminescence complementation assay for RGS: G protein interactions in cells.Analytical biochemistry · 2017Article
- Building Graphs To Describe Dynamics, Kinetics, and Energetics in the d-ALa:d-Lac Ligase VanA.Journal of chemical information and modeling · 2016Article
- NMR Methods to Study Dynamic Allostery.PLoS computational biology · 2016Review
- Theoretical and computational studies of peptides and receptors of the insulin family.Membranes · 2015Review
- Two pathways mediate interdomain allosteric regulation in pin1.Structure (London, England : 1993) · 2015Article
- Direct and Propagated Effects of Small Molecules on Protein-Protein Interaction Networks.Frontiers in bioengineering and biotechnology · 2015Review
- Structural Model of the Bilitranslocase Transmembrane Domain Supported by NMR and FRET Data.PloS one · 2015Article
- Extended Phase-Space Methods for Enhanced Sampling in Molecular Simulations: A Review.Frontiers in bioengineering and biotechnology · 2015Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Gα-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations and NMR spectroscopy, we have studied in molecular detail the mechanism of action of CCG-50014, a potent small molecule inhibitor of RGS4 that covalently binds to cysteine residues on RGS4. We apply temperature-accelerated molecular dynamics (TAMD) to carry out enhanced conformational sampling of apo RGS4 structures, and consistently find that the α5-α6 helix pair of RGS4 can spontaneously span open-like conformations, allowing binding of CCG-50014 to the buried side-chain of Cys95. Both NMR experiments and MD simulations reveal chemical shift perturbations in residues in the vicinity of inhibitor binding site as well as in the RGS4-Gα binding interface. Consistent with a loss of G-protein binding, GAP activity, and allosteric mechanism of action of CCG-50014, our simulations of the RGS4-Gα complex in the presence of inhibitor suggest a relatively unstable protein-protein interaction. These results have potential implications for understanding how the conformational dynamics among RGS proteins may play a key role in the sensitivity of inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.