Ankyrin repeat proteins - Isis Project No 1566

Assays for inhibitors which alter the function of ankyrin repeat proteins, with potential use in the inflammation response

The Background

The Ankyrin repeat is a very common structural motif involved in protein-protein interactions. The ankyrin repeat motif has been found in proteins of very diverse function such as transcriptional initiators and regulators, cell-cycle regulators, developmental regulators, cytoskeletal organizers, ion transporters and signal transducers, and even toxins.  Proteins containing the ankyrin repeat motif are central to the inflammatory response. 

Currently, over 3500 sequences containing ankyrin structural motifs can be found listed in the SMART domain database (Shultz et al. PNAS (1998) 95 5857-5864). Over 600 human proteins containing ankyrin repeat units are known. Many ankyrin proteins are also present in plants where they are involved in regulation and signaling.

The Oxford Invention

In the inflammation response pathways, the protein IkB-a interacts with the transcription factor NFkB and prevents its nuclear translocation.  When IkB-a  is degraded and its cellular concentration levels are low, free NFkB is translocated to the nucleus where it associates with various activators and initiates the transcription of many genes involved in the inflammatory response. Researchers at Oxford have now discovered that the enzyme FIH hydroxylates several proteins containing the ankyrin repeat motif and which are involved in the inflammatory response. 

The Oxford invention provides assays for inhibitors of the enzymatic hydroxylation of ankyrin repeat proteins.  Inhibitors identified through the assays may modify the activity of the ankyrin repeat proteins so that their stability is altered, making the inhibitors useful in treatments of diseases associated with the inflammatory response.  The assays are also useful in selectivity screens for FIH inhibitors aimed at other targets.

Commercial Opportunity & Patent Status

A patent application has been filed to protect this work. Isis wishes to talk to companies interested in developing the commercial opportunities for this technology. Please contact the Isis Project Manager to discuss this further.

Key words

inflammation, protein inhibitors, assays

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