ArticleThe Journal of biological chemistry2010
Proteins at work: a combined small angle X-RAY scattering and theoretical determination of the multiple structures involved on the protein kinase functional landscape.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Engineering a Stable Grb2 Monomer: The W60A Mutation Disrupts Dimerization but Preserves Structural Integrity.ACS omega · 2026Article
- Biophysical and Integrative Characterization of Protein Intrinsic Disorder as a Prime Target for Drug Discovery.Biomolecules · 2023Review
- Evolving SAXS versatility: solution X-ray scattering for macromolecular architecture, functional landscapes, and integrative structural biology.Current opinion in structural biology · 2019Review
- Dynamic regulatory features of the protein tyrosine kinases.Biochemical Society transactions · 2019Review
- The role of small-angle scattering in structure-based screening applications.Biophysical reviews · 2018Review
- Atomistic structural ensemble refinement reveals non-native structure stabilizes a sub-millisecond folding intermediate of CheY.Scientific reports · 2017Article
- Domain interactions of C-terminal Src Kinase determined through NMR spectroscopy with segmental isotope labeling.Protein & cell · 2017Article
- Comparison of native and non-native ubiquitin oligomers reveals analogous structures and reactivities.Protein science : a publication of the Protein Society · 2016Article
- Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation.PloS one · 2015Article
- Article
- Methods for SAXS-based structure determination of biomolecular complexes.Advanced materials (Deerfield Beach, Fla.) · 2014Article
- Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Fast-SAXS-pro: a unified approach to computing SAXS profiles of DNA, RNA, protein, and their complexes.The Journal of chemical physics · 2013Article
- Distal loop flexibility of a regulatory domain modulates dynamics and activity of C-terminal SRC kinase (csk).PLoS computational biology · 2013Article
- Allosteric activation transitions in enzymes and biomolecular motors: insights from atomistic and coarse-grained simulations.Topics in current chemistry · 2013Review
- The shadow map: a general contact definition for capturing the dynamics of biomolecular folding and function.The journal of physical chemistry. B · 2012Article
- Article
- Substrate-specific reorganization of the conformational ensemble of CSK implicates novel modes of kinase function.PLoS computational biology · 2012Article
- Excited states of ribosome translocation revealed through integrative molecular modeling.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Macromolecular assembly of polycystin-2 intracytosolic C-terminal domain.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
C-terminal Src kinase (Csk) phosphorylates and down-regulates the Src family tyrosine kinases (SFKs). Crystallographic studies of Csk found an unusual arrangement of the SH2 and SH3 regulatory domains about the kinase core, forming a compact structure. However, recent structural studies of mutant Csk in the presence of an inhibitor indicate that the enzyme accesses an expanded structure. To investigate whether wt-Csk may also access open conformations we applied small angle x-ray scattering (SAXS). We find wt-Csk frequently occupies an extended conformation where the regulatory domains are removed from the kinase core. In addition, all-atom structure-based simulations indicate Csk occupies two free energy basins. These basins correspond to ensembles of distinct global conformations of Csk: a compact structure and an extended structure. The transitions between these structures are entropically driven and accessible via thermal fluctuations that break local interactions. We further characterized the ensemble by generating theoretical scattering curves for mixed populations of conformations from both basins and compared the predicted scattering curves to the experimental profile. This population-combination analysis is more consistent with the experimental data than any rigid model. It suggests that Csk adopts a broad ensemble of conformations in solution, populating extended conformations not observed in the crystal structure that may play an important role in the regulation of Csk. The methodology developed here is broadly applicable to biological macromolecules and will provide useful information about what ensembles of conformations are consistent with the experimental data as well as the ubiquitous dynamic reversible assembly processes inherent in biology.
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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.