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Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2.
Jake W Anderson1, David Vaisar1, David N Jones2
1Department of Biochemistry, University of Colorado, Boulder, CO.
Biorxiv : the Preprint Server for Biology
|September 25, 2023
Summary
Researchers identified 14 new extracellular signal-regulated kinase (ERK) inhibitors that stabilize the active "R" conformation. This conformation selection impacts distal regions and offers new strategies for modulating ERK substrate interactions.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Extracellular signal-regulated kinase-2 (ERK2) activation involves dynamic conformational changes between
- L
- and
- R
- states, with the
- R
- state linked to catalysis.
- ATP-competitive inhibitors like Vertex-11e can select for the
- R
- -state, influencing the activation loop and allosterically coupled active site dynamics.
Conclusions:
- A model for the R-state is proposed, involving N-lobe movements that enhance active site compactness and alter activation loop dynamics.
- Conformation selection properties of inhibitors can be leveraged to modulate the protein docking interface for ERK substrates and effectors.
- These findings provide insights into the rational design of ERK inhibitors with specific conformational preferences.
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