Language
English
Publication Date
1-23-2026
Journal
International Journal of Molecular Sciences
DOI
10.3390/ijms27031143
PMID
41683573
PMCID
PMC12898022
PubMedCentral® Posted Date
1-23-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Fyn is a Src-family tyrosine kinase implicated in synaptic dysfunction and neuroinflammation across multiple neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Saracatinib (AZD0530) is a potent Src-family inhibitor that has been explored as a repurposed therapeutic; however, its clinical utility is limited by poor kinase selectivity caused by high sequence conservation within Src-family ATP-binding sites. Here, we combine surface plasmon resonance (SPR) and X-ray crystallography to define saracatinib recognition by the Fyn kinase domain (KD). SPR single-cycle kinetics shows that saracatinib binds the isolated Fyn KD and full-length Fyn with low-nanomolar affinity, whereas dasatinib binds with subnanomolar affinity and markedly slower dissociation. We determined the crystal structure of the Fyn KD-saracatinib complex at 2.22 Å resolution. The kinase adopts an active-like conformation with the DFG motif and αC-helix in the 'in' state and a conserved β3 αC Lys-Glu salt bridge. Saracatinib occupies the adenine and ribose pockets, and engages the hinge through direct and water-mediated hydrogen bonding while complementing a hydrophobic back pocket by van der Waals contacts. Comparison with reported saracatinib-bound structures of other kinases suggests that the active-state geometry observed for Fyn creates a pocket not observed in inactive-like complexes, providing a structural handle for designing Fyn-selective inhibitors. Comparison with all saracatinib-bound kinase co-structures currently available in the PDB (ALK2 and PKMYT1) indicates a conserved monodentate hinge binding mode but kinase-dependent αC-helix conformations, providing a structural rationale for designing Fyn-selective analogues.
Keywords
Proto-Oncogene Proteins c-fyn, Benzodioxoles, Quinazolines, Humans, Crystallography, X-Ray, Protein Binding, Models, Molecular, Protein Kinase Inhibitors, Binding Sites, Surface Plasmon Resonance, Protein Conformation, Fyn, Src-family kinase, saracatinib, AZD0530, dasatinib, X-ray crystallography, surface plasmon resonance, neurodegeneration, kinase inhibitor selectivity, Tau, Tauopathy
Published Open-Access
yes
Recommended Citation
Ta, Hai Minh; Sankaran, Banumathi; Roush, Eric D; et al., "Fyn-Saracatinib Complex Structure Reveals an Active State-like Conformation" (2026). Faculty, Staff and Students Publications. 8034.
https://digitalcommons.library.tmc.edu/baylor_docs/8034