Journal article
“DFG-Flip” in the Insulin Receptor Kinase Is Facilitated by a Helical Intermediate State of the Activation Loop
Biophysical journal, v 102(8), pp 1979-1987
18 Apr 2012
PMID: 22768955
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
We have characterized a large-scale inactive-to-active conformational change in the activation-loop of the insulin receptor kinase domain at the atomistic level via untargeted temperature-accelerated molecular dynamics (TAMD) and free-energy calculations using the string method. TAMD simulations consistently show folding of the A-loop into a helical conformation followed by unfolding to an active conformation, causing the highly conserved DFG-motif (Asp
1150
, Phe
1151
, and Gly
1152
) to switch from the inactive “D-out/F-in” to the nucleotide-binding-competent “D-in/F-out” conformation. The minimum free-energy path computed from the string method preserves these helical intermediates along the inactive-to-active path, and the thermodynamic free-energy differences are consistent with previous work on various other kinases. The mechanisms revealed by TAMD also suggest that the regulatory spine can be dynamically assembled/disassembled either by DFG-flip or by movement of the
α
C-helix. Together, these findings both broaden our understanding of kinase activation and point to intermediates as specific therapeutic targets.
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Details
- Title
- “DFG-Flip” in the Insulin Receptor Kinase Is Facilitated by a Helical Intermediate State of the Activation Loop
- Creators
- Harish Vashisth - Department of Chemistry and Biophysics, University of Michigan, Ann Arbor, MichiganLuca Maragliano - Department of Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, Genoa, ItalyCameron F Abrams - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania
- Publication Details
- Biophysical journal, v 102(8), pp 1979-1987
- Publisher
- The Biophysical Society
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000303003300033
- Scopus ID
- 2-s2.0-84859922106
- Other Identifier
- 991014877967204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biophysics