10DJ

Fyn Kinase Domain-Saracatinib Complex Structure

Summary for 10DJ

• Entry DOI: 10.2210/pdb10dj/pdb
• Descriptor: Tyrosine-protein kinase Fyn, N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-[2-(4-METHYLPIPERAZIN-1-YL)ETHOXY]-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE (3 entities in total)
• Functional Keywords: tyrosine-protein kinase fyn, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65830.44

Authors

Ta, H.M.,MacKenzie, K.,Ferreon, J.C.,Ferreon, A.C.,Kim, C. (deposition date: 2026-01-13, release date: 2026-03-18, Last modification date: 2026-03-25)

Primary citation

Ta, H.M.,Sankaran, B.,Roush, E.D.,Ferreon, J.C.,Ferreon, A.C.M.,Kim, C.
Fyn-Saracatinib Complex Structure Reveals an Active State-like Conformation.
Int J Mol Sci, 27:-, 2026

PubMed 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.

PubMed: 41683573
DOI: 10.3390/ijms27031143

Experimental method

X-RAY DIFFRACTION (2.22 Å)