Type II Binders Targeting the "GLR-Out" Conformation of the Pseudokinase STRADα
Ryan H B Smith1,2, Zaigham M Khan2, Peter Man-Un Ung1
1Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Biochemistry
|January 13, 2021
Summary
Pseudokinases, like STRADα, can be targeted with specific drugs. This study shows conformation-specific inhibitors can bind pseudokinases, opening new therapeutic avenues.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- Pseudokinases are crucial for cellular signaling but their drug targeting is poorly understood.
- They share similarities with active kinases but their conformational flexibility and drug interactions are not well characterized.
Purpose of the Study:
- To investigate the pharmacological potential of pseudokinases using STRADα as a model.
- To explore the use of conformation-specific inhibitors for pseudokinase drug development.
Main Methods:
- Utilized integrated structural modeling to generate a "GLR-out" conformational ensemble for STRADα.
- Performed virtual screening to identify potential type II inhibitors binding to this ensemble.
- Validated compound binding using biophysical techniques like protein thermal stabilization and ATP competition assays.
Main Results:
- Identified and validated type II compounds that bind to the "GLR-out" conformation of STRADα.
- Demonstrated that STRADα can adopt inactive conformations and interact with conformation-specific inhibitors.
- Surface methylation confirmed the binding of a top-performing compound, supporting the "GLR-out" model.
Conclusions:
- Pseudokinases, despite lacking catalytic activity, retain conformational dynamics similar to active kinases.
- Conformation-specific inhibitors show promise for targeting pseudokinases, including STRADα.
- This research expands the druggability landscape of pseudokinases for therapeutic interventions.
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