# Fyn–Saracatinib Complex Structure Reveals an Active State-like Conformation

## TL;DR

This study reveals how the drug saracatinib binds to the Fyn kinase in a way that could help design more selective treatments for neurodegenerative diseases.

## Contribution

The paper provides a high-resolution structure of the Fyn–saracatinib complex in an active-like conformation, offering insights for designing Fyn-selective inhibitors.

## Key findings

- Saracatinib binds the Fyn kinase domain with low-nanomolar affinity and adopts an active-like conformation.
- The structure reveals a conserved hinge binding mode and a unique hydrophobic pocket for Fyn, distinct from other saracatinib-bound kinases.
- Comparison with other structures suggests a structural basis for developing Fyn-specific drug analogs.

## 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.