An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering
Copyright policy )An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering
Allostery is an inherent feature of proteins, but it remains challenging to reveal the mechanisms by which allosteric signals propagate. A clearer understanding of this intrinsic circuitry would afford new opportunities to modulate protein function. Here, we have identified allosteric sites in protein tyrosine phosphatase 1B (PTP1B) by combining multiple-temperature X-ray crystallography experiments and structure determination from hundreds of individual small-molecule fragment soaks. New modeling approaches reveal 'hidden' low-occupancy conformational states for protein and ligands. Our results converge on allosteric sites that are conformationally coupled to the active-site WPD loop and are hotspots for fragment binding. Targeting one of these sites with covalently tethered molecules or mutations allosterically inhibits enzyme activity. Overall, this work demonstrates how the ensemble nature of macromolecular structure, revealed here by multitemperature crystallography, can elucidate allosteric mechanisms and open new doors for long-range control of protein function.
- Utrecht University Netherlands
- Science for Life Laboratory Sweden
- University of Johannesburg South Africa
- SUNY at Buffalo United States
- University of California, San Francisco United States
Models, Molecular, Biomedical and clinical sciences, Protein Conformation, Structural Biology and Molecular Biophysics, Crystallography, X-Ray, Temperature (mesh), Allosteric Regulation (mesh), Models, 31 Biological sciences (for-2020), Protein Binding (mesh), structural biology, Biology (General), Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Humans (mesh), Crystallography, allostery, Mutation (mesh), Q, R, Temperature, Biological Sciences, Biological sciences, Molecular (mesh), protein dynamics, Medicine, Kinetics (mesh), Allosteric Site, Protein Binding, 570, QH301-705.5, 1.1 Normal biological development and functioning, Science, Allosteric Site (mesh), 0601 Biochemistry and Cell Biology (for), 612, Binding Sites (mesh), Non-Receptor Type 1 (mesh), phosphatase, Allosteric Regulation, 42 Health sciences (for-2020), molecular biophysics, Humans, X-Ray (mesh), human, 1.1 Normal biological development and functioning (hrcs-rac), 31 Biological Sciences (for-2020), Protein Conformation (mesh), Binding Sites, E. coli, 500, Health sciences, Molecular, 540, 3101 Biochemistry and Cell Biology (for-2020), Kinetics, 32 Biomedical and clinical sciences (for-2020), Mutation, X-Ray, Biochemistry and Cell Biology, Protein Tyrosine Phosphatase
Models, Molecular, Biomedical and clinical sciences, Protein Conformation, Structural Biology and Molecular Biophysics, Crystallography, X-Ray, Temperature (mesh), Allosteric Regulation (mesh), Models, 31 Biological sciences (for-2020), Protein Binding (mesh), structural biology, Biology (General), Non-Receptor Type 1, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Humans (mesh), Crystallography, allostery, Mutation (mesh), Q, R, Temperature, Biological Sciences, Biological sciences, Molecular (mesh), protein dynamics, Medicine, Kinetics (mesh), Allosteric Site, Protein Binding, 570, QH301-705.5, 1.1 Normal biological development and functioning, Science, Allosteric Site (mesh), 0601 Biochemistry and Cell Biology (for), 612, Binding Sites (mesh), Non-Receptor Type 1 (mesh), phosphatase, Allosteric Regulation, 42 Health sciences (for-2020), molecular biophysics, Humans, X-Ray (mesh), human, 1.1 Normal biological development and functioning (hrcs-rac), 31 Biological Sciences (for-2020), Protein Conformation (mesh), Binding Sites, E. coli, 500, Health sciences, Molecular, 540, 3101 Biochemistry and Cell Biology (for-2020), Kinetics, 32 Biomedical and clinical sciences (for-2020), Mutation, X-Ray, Biochemistry and Cell Biology, Protein Tyrosine Phosphatase
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