Nature of the Pre-Chemistry Ensemble in Mitogen-Activated Protein Kinases |
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Affiliation: | 1. Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01003, USA;2. Department of Hematology, The Central Hospital of Taizhou, Taizhou, Zhejiang 318000, PR China;3. Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA 01003, USA;1. Department of Chemistry, University of Toronto, Toronto, Canada;2. Molecular Biotechnology, University of Potsdam, Potsdam, Germany;1. IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal;2. i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal;3. Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA;4. Centre de Biophysique Moléculaire, CNRS UPR430, Orléans, France |
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Abstract: | In spite of the availability of a significant amount of structural detail on docking interactions involving mitogen-activated protein kinases (MAPKs) and their substrates, the mechanism by which the disordered phospho-acceptor on the substrate transiently interacts with the kinase catalytic elements and is phosphorylated, often with high efficiency, remains poorly understood. Here, this dynamic interaction is analyzed in the context of available biophysical and biochemical data for ERK2, an archetypal MAPK. A hypothesis about the nature of the ternary complex involving a MAPK, its substrate, and ATP immediately prior to the chemical step (the pre-chemistry complex) is proposed. It is postulated that the solution ensemble (the pre-chemistry ensemble) representing the pre-chemistry complex comprises several conformations that are linked by dynamics on multiple timescales. These individual conformations possess different intrinsic abilities to proceed through the chemical step. The overall rate of chemistry is therefore related to the microscopic nature of the pre-chemistry ensemble, its constituent conformational microstates, and their intrinsic abilities to yield a phosphorylated product. While characterizing these microstates within the pre-chemistry ensemble in atomic or near-atomic detail is an extremely challenging proposition, recent developments in hybrid methodologies that employ computational approaches driven by experimental data appear to provide the most promising path forward toward achieving this goal. |
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