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Role of Protein Dynamics in Allosteric Control of the Catalytic Phosphoryl Transfer of Insulin Receptor Kinase
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Cluster (CLiC).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Cluster (CLiC).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Cluster (CLiC).
2015 (Engelska)Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, nr 39, s. 12454-12457Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2015. Vol. 137, nr 39, s. 12454-12457
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-110998DOI: 10.1021/jacs.5b07996ISI: 000362628300009PubMedID: 26374925OAI: oai:DiVA.org:umu-110998DiVA, id: diva2:871899
Tillgänglig från: 2015-11-17 Skapad: 2015-11-02 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Ingår i avhandling
1. Understanding molecular mechanisms of protein tyrosine kinases by molecular dynamics and free energy calculations
Öppna denna publikation i ny flik eller fönster >>Understanding molecular mechanisms of protein tyrosine kinases by molecular dynamics and free energy calculations
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background: Insulin receptor kinase (IRK) and Insulin-like growth factor 1 receptor kinase (IGF-1RK) are two important members in the large class of tyrosine kinase receptors. They play pivotalroles in the regulation of glucose homeostasis, cell proliferation, differentiation, motility, andtransformation. Their dysfunctions are linked to diabetes, rheumatoid arthritis and many cancers.Although their regulatory mechanisms have been widely studied experimentally, the atomisticdetails are still poorly understood, especially for the influences caused by activation loop (A-loop)phosphorylation.Methods: Molecular dynamics (MD) and alchemical free energy simulations are carried out tounderstand mechanisms underlying the kinase proteins regulation and their thermodynamic basis.To capture a full picture about the entire kinase catalytic cycle, different functional steps areconsidered, i.e., conformational transition, substrate binding, phosphoryl transfer and productrelease. The effects of the A-loop phosphorylation on protein’s dynamics, structure, stability, andfree energy landscape are examined by various analysis methods, including principle componentanalysis (PCA), motion projection, dynamical network analysis and free energy perturbation.Results: The main findings are: 1) A-loop phosphorylation shifts the kinase conformationalpopulation to the active one by changing the electrostatic environments in the kinase apo form, 2)allosterically fine-tunes the orientation of the catalytic residues mediated by the >C-helix in thereactant and product binding states, and 3) thermodynamically favors the kinase catalysis presentedby a catalytic-cycle-mimic free energy landscape. An integrated view on the roles of A-loopphosphorylation in kinase allostery is developed by incorporating kinase’s dynamics, structuralinteractions, thermodynamics and free energy landscape. In addition, new soft-core potentials(Gaussian soft-core) and protocols are developed to conduct accurate and efficient alchemical freeenergy calculations.Conclusions: The entire catalytic cycle is examined by MD and free energy calculations andcomprehensive analyses are conducted. The findings from the studied kinases are general and canbe implemented to the other members in IRK family or even to more non-homologous familiesbecause of the conservation of the characteristic residues between their A-loop and >C-helix. Inaddition, the Gaussian soft-core potentials provide a new tool to perform alchemical free energycalculations in an efficient way.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2017. s. 66
Nyckelord
kinase, IRK, IGF-1RK, phosphorylation, activation loop, molecular dynamics, phosphoryl transfer, alchemical free energy, dynamical network, correlation map, PCA, motion projection, Gaussian softcore, free energy landscape, kinase catalysis
Nationell ämneskategori
Teoretisk kemi
Identifikatorer
urn:nbn:se:umu:diva-134867 (URN)978-91-7601-727-2 (ISBN)
Disputation
2017-06-09, Stora hörsalen, KBE303, KBC-huset, 901 87 Umeå, Sweden, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-05-19 Skapad: 2017-05-14 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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