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Role of Protein Dynamics in Allosteric Control of the Catalytic Phosphoryl Transfer of Insulin Receptor Kinase
Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational Life Science Cluster (CLiC).
Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational Life Science Cluster (CLiC).
Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational Life Science Cluster (CLiC).
2015 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, no 39, 12454-12457 p.Article in journal (Refereed) Published
Abstract [en]

The catalytic and allosteric mechanisms of insulin receptor kinase (IRK) are investigated by a combination of ab initio and semiempirical quantum mechanical and molecular mechanical (QM/MM) methods and classical molecular dynamics (MD) simulations. The simulations reveal that the catalytic reaction proceeds in two steps, starting with the transfer of a proton from substrate Tyr to the catalytic Asp1132, followed by the phosphoryl transfer from ATP to substrate Tyr. The enhancement of the catalytic rate of IRK upon phosphorylations in the enzyme's activation loop is found to occur mainly via changes to the free energy landscape of the proton transfer step, favoring the proton transfer in the fully phosphorylated enzyme. In contrast, the effects of the phosphorylations on the phosphoryl transfer are smaller. Equilibrium MD simulations show that IRK phosphorylations affect the protein dynamics of the enzyme before the proton transfer to Asp1132 with only a minor effect after the proton transfer. This finding is consistent with the large change in the proton transfer free energy and the smaller change in the free energy barrier of phosphoryl transfer found by QM/MM simulations. Taken together, the present results provide details on how IRK phosphorylation exerts allosteric control of the catalytic activity via modifications of protein dynamics and free energy landscape of catalytic reaction. The results also highlight the importance of protein dynamics in connecting protein allostery and catalysis to control catalytic activity of enzymes.

Place, publisher, year, edition, pages
2015. Vol. 137, no 39, 12454-12457 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-110998DOI: 10.1021/jacs.5b07996ISI: 000362628300009PubMedID: 26374925OAI: oai:DiVA.org:umu-110998DiVA: diva2:871899
Available from: 2015-11-17 Created: 2015-11-02 Last updated: 2015-11-17Bibliographically approved

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