Imperial College London

ProfessorPaulFrench

Faculty of Natural SciencesDepartment of Physics

Professor of Physics and Vice Dean (Research) - FoNS
 
 
 
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Contact

 

+44 (0)20 7594 7706paul.french Website

 
 
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Assistant

 

Ms Judith Baylis +44 (0)20 7594 7713

 
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Location

 

609Blackett LaboratorySouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Perdios:2017:10.1038/srep39841,
author = {Perdios, L and Lowe, AR and Saladino, G and Bunney, TD and Thiyagarajan, N and Alexandrov, Y and Dunsby, C and French, PM and Chin, JW and Gervasio, FL and Tate, EW and Katan, M},
doi = {10.1038/srep39841},
journal = {Scientific Reports},
title = {Conformational transition of FGFR kinase activation revealed by site-specific unnatural amino acid reporter and single molecule FRET},
url = {http://dx.doi.org/10.1038/srep39841},
volume = {7},
year = {2017}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Protein kinases share significant structural similarity; however, structural features alone are insufficient to explain their diverse functions. Thus, bridging the gap between static structure and function requires a more detailed understanding of their dynamic properties. For example, kinase activation may occur via a switch-like mechanism or by shifting a dynamic equilibrium between inactive and active states. Here, we utilize a combination of FRET and molecular dynamics (MD) simulations to probe the activation mechanism of the kinase domain of Fibroblast Growth Factor Receptor (FGFR). Using genetically-encoded, site-specific incorporation of unnatural amino acids in regions essential for activation, followed by specific labeling with fluorescent moieties, we generated a novel class of FRET-based reporter to monitor conformational differences corresponding to states sampled by non phosphorylated/inactive and phosphorylated/active forms of the kinase. Single molecule FRET analysis in vitro, combined with MD simulations, shows that for FGFR kinase, there are populations of inactive and active states separated by a high free energy barrier resulting in switch-like activation. Compared to recent studies, these findings support diversity in features of kinases that impact on their activation mechanisms. The properties of these FRET-based constructs will also allow further studies of kinase dynamics as well as applications in vivo.
AU - Perdios,L
AU - Lowe,AR
AU - Saladino,G
AU - Bunney,TD
AU - Thiyagarajan,N
AU - Alexandrov,Y
AU - Dunsby,C
AU - French,PM
AU - Chin,JW
AU - Gervasio,FL
AU - Tate,EW
AU - Katan,M
DO - 10.1038/srep39841
PY - 2017///
SN - 2045-2322
TI - Conformational transition of FGFR kinase activation revealed by site-specific unnatural amino acid reporter and single molecule FRET
T2 - Scientific Reports
UR - http://dx.doi.org/10.1038/srep39841
UR - http://www.ncbi.nlm.nih.gov/pubmed/28045057
UR - http://hdl.handle.net/10044/1/43641
VL - 7
ER -