NDLI: 3-D structure and dynamics of protein kinase B—new mechanism for the allosteric regulation of an AGC kinase

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3-D structure and dynamics of protein kinase B—new mechanism for the allosteric regulation of an AGC kinase

Content Provider	Springer Nature Link
Author	Calleja, Véronique Laguerre, Michel Larijani, Banafshé
Copyright Year	2009
Abstract	New developments regarding the structure and in vivo dynamics of protein kinase B (PKB/Akt) have been recently exposed. Here, we specifically review how the use of multi-disciplinary approaches has resulted in reaching the recent progress made to relate the quaternary structure of PKB to its in vivo function. Using X-ray crystallography, the structure of PKB pleckstrin homology (PH) and kinase domains was determined separately. The molecular mechanisms involved in (a) the binding of the phosphoinositides to the PH domain and (b) the activation of the kinase with the rearrangement of the catalytic site and substrate binding were determined. In vitro, nuclear magnetic resonance and circular dychroism studies gave complementary information on the interaction of the PH domain with the phosphoinositides. However, the molecular nature and the function of the interactions between the PKB domains could not be deduced from the X-ray data since the full-length PKB has not been crystallised. In vitro, dynamic information on the inter-domain conformational changes related to PKB activation states emerged with the use of tandem mass spectrometry. Cell imaging and Förster resonance energy transfer provided in vivo dynamics. Molecular modelling and dynamic simulations in conjunction with mutagenesis and biochemical analysis were used to investigate the complex interactions between the PKB domains in vivo and understand at the molecular level how it linked to its activity. The compilation of the information obtained on the 3-D structure and the spatiotemporal dynamics of this widely studied oncogene could be applied to the study of other proteins. This inter-disciplinary approach led to a more profound understanding of PKB complex activation mechanism in vivo that will shed light onto new ideas and possibilities for modulating its activity.
Starting Page	11
Ending Page	25
Page Count	15
File Format	PDF
ISSN	18646158
Journal	Journal of Chemical Biology
Volume Number	2
Issue Number	1
e-ISSN	18646166
Language	English
Publisher	Springer-Verlag
Publisher Date	2009-02-20
Publisher Place	Berlin, Heidelberg
Access Restriction	Subscribed
Subject Keyword	Protein kinase B Akt 3-D structure Molecular modelling Dynamics Multi-disciplinary approach FRET/FLIM Biochemistry Pharmacology/Toxicology Cell Biology Biophysics/Biomedical Physics Physical Chemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Biophysics

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