TWEAK is a multifunctional cytokine controlling many cellular activities. TWEAK acts by binding to Fn14, a member of the TNFR superfamily. Dysregulation of TWEAK-Fn14 signaling is observed in a number of disease states including cancer. Activation of Fn14 by TWEAK triggers cancer cell invasion and survival, thus representing an attractive pathway for therapeutic intervention.This contribution elucidates key structural elements of the TWEAK-Fn14 interaction to guide early drug discovery efforts. The Fn14 cysteine rich domain (CRD) is well documented by an NMR solution structure and functional mutation studies by Winkles. To supplement that information, six structural models of TWEAK are built based on experimental structures of low homology templates from the TNF superfamily. Protein-protein docking, followed by data-driven prioritization, yields two promising TWEAK-Fn14 binding hypotheses. Mutagenesis analysis confirms one hypothesis, providing a novel structural basis for target-based identification of small molecule inhibitors of the TWEAK-FN14 interaction.

Structural recognition between TWEAK and Fn14: A prelude to discovery of inhibitors for Fn14-TWEAK association

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.