The Target Enabling Package (TEP) programme's foundation is built upon the recognition that genetic data is proving to be a powerful tool for target validation. As such, TEPs provide a critical mass of reagents and knowledge on a protein target to allow rapid biochemical and chemical exploration and characterisation of proteins with genetic linkage to key disease areas. TEPs provide an answer to the missing link between genomics and chemical biology, provide a starting point for chemical probe generation and therefore catalyse new biology and disease understanding with the ultimate aim of enabling translation collaborations and target/ drug discovery.
We are committed to generating and making available 24 high-quality TEPs by June 2020.SUMMARY OF PROJECT
Kinases WNK1-4 regulate cation-chloride cotransporters via phosphorylation of SPAK and OSR1 and thereby
control salt homeostasis, cell volume and blood pressure. Gain of function mutations in WNK kinases are
found in Gordon’s hypertension syndrome suggesting the WNK pathway as a therapeutic target. WNK3
inhibition in particular has also been shown to reduce cerebral injury after Ischemic stroke. Here we present
assays and crystal structures that define (i) the molecular basis for disease mutations; (ii) the multiple
functional domains of WNK kinases and their protein interactions; (iii) the binding of small molecule kinase
inhibitors and a potential allosteric pocket.The work performed at the SGC has been funded by a grant from the Wellcome [106169/ZZ14/Z]
