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Protein Allostery at Atomic Resolution |
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| Authors: | Dr Dean Strotz Dr Julien Orts Dr Harindranath Kadavath Dr Michael Friedmann Dhiman Ghosh Dr Simon Olsson Dr Celestine N Chi Aditya Pokharna Prof Dr Peter Güntert Dr Beat Vögeli Prof Dr Roland Riek |
| Institution: | 1. Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, 8093 Zürich, Switzerland;2. Department of Mathematics and Computer Science, Freie Universität Berlin, Arnimallee 6, 14195 Berlin, Germany;3. Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden;4. Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, 8093 Zürich, Switzerland
Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, and Frankfurt Institute for Advanced Studies, J.W. Goethe-Universität, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo, 192-0397 Japan;5. Department of Biochemistry and Molecular Genetics, University of Colorado at Denver, 12801 East 17th Avenue, Aurora, CO, 80045 USA |
| Abstract: | Protein allostery is a phenomenon involving the long range coupling between two distal sites in a protein. In order to elucidate allostery at atomic resoluion on the ligand-binding WW domain of the enzyme Pin1, multistate structures were calculated from exact nuclear Overhauser effect (eNOE). In its free form, the protein undergoes a microsecond exchange between two states, one of which is predisposed to interact with its parent catalytic domain. In presence of the positive allosteric ligand, the equilibrium between the two states is shifted towards domain–domain interaction, suggesting a population shift model. In contrast, the allostery-suppressing ligand decouples the side-chain arrangement at the inter-domain interface thereby reducing the inter-domain interaction. As such, this mechanism is an example of dynamic allostery. The presented distinct modes of action highlight the power of the interplay between dynamics and function in the biological activity of proteins. |
| Keywords: | allostery ligand binding NMR spectroscopy protein dynamics protein structure |