Defining the conformational landscape of glycogen synthase kinase 3 beta (GSK3β)
- 1Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX77555, USA
- 2Sealy Center for Environmental Health and Medicine, The University of Texas Medical Branch, Galveston, TX77555, USA
Abstract
Glycogen synthase kinase 3 beta (GSK3β) is a serine/threonine kinase implicated in Alzheimer’s disease, type 2 diabetes, oncology and bipolar disorder, and represents an extensively pursued therapeutic target. Despite the substantial accumulation of GSK3β crystal structures in the Protein Data Bank (PDB), no systematic consolidation and conformational analysis of this dataset have been performed. Here, we manually classified all deposited GSK3β crystal structures, comprising 111 unique PDB entries and 88 distinct co-crystallized ligands (data extracted March 11th, 2026). Using the pre-existing KinCoRe dataset and standardized nomenclature, we assigned conformational states across the complete GSK3β structural ensemble and evaluated their relationships with bound ligands. All structures adopt the DFG-in kinase conformation but populate eight distinct conformational substates defined by combinations of activation-loop geometry, αC-helix orientation, regulatory salt-bridge status, αC–β5-loop and phosphorylation state. Our structural analysis reveals that chemically distinct Type I inhibitors stabilize distinct conformational substates, including variation in activation-loop arrangement and activity-like states. These relationships have not previously been characterized across the complete GSK3β crystal structure ensemble. This work provides the first comprehensive conformational landscape of resolved GSK3β crystal structures, a curated structural reference to guide the selection of potentially biologically relevant conformations for structure-based drug design and a systematic framework for analogous kinase-wide conformational analyses.
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BibTeX
@article{gurtu2026defining,
title = {{Defining the conformational landscape of glycogen synthase kinase 3 beta (GSK3β)}},
author = {Akanksha Gurtu and Fernanda Laezza},
journal = {Acta Crystallographica Section D: Structural Biology},
year = {2026},
month = oct,
doi = {10.1107/s2059798326010533},
url = {https://doi.org/10.1107/s2059798326010533},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Defining the conformational landscape of glycogen synthase kinase 3 beta (GSK3β)
AU - Akanksha Gurtu
AU - Fernanda Laezza
PY - 2026
DA - 2026/10/23
JO - Acta Crystallographica Section D: Structural Biology
DO - 10.1107/s2059798326010533
UR - https://doi.org/10.1107/s2059798326010533
AB - Glycogen synthase kinase 3 beta (GSK3β) is a serine/threonine kinase implicated in Alzheimer’s disease, type 2 diabetes, oncology and bipolar disorder, and represents an extensively pursued therapeutic target. Despite the substantial accumulation of GSK3β crystal structures in the Protein Data Bank (PDB), no systematic consolidation and conformational analysis of this dataset have been performed. Here, we manually classified all deposited GSK3β crystal structures, comprising 111 unique PDB entries and 88 distinct co-crystallized ligands (data extracted March 11th, 2026). Using the pre-existing KinCoRe dataset and standardized nomenclature, we assigned conformational states across the complete GSK3β structural ensemble and evaluated their relationships with bound ligands. All structures adopt the DFG-in kinase conformation but populate eight distinct conformational substates defined by combinations of activation-loop geometry, αC-helix orientation, regulatory salt-bridge status, αC–β5-loop and phosphorylation state. Our structural analysis reveals that chemically distinct Type I inhibitors stabilize distinct conformational substates, including variation in activation-loop arrangement and activity-like states. These relationships have not previously been characterized across the complete GSK3β crystal structure ensemble. This work provides the first comprehensive conformational landscape of resolved GSK3β crystal structures, a curated structural reference to guide the selection of potentially biologically relevant conformations for structure-based drug design and a systematic framework for analogous kinase-wide conformational analyses.
SN - 2059-7983
ER -