Antibody-assisted Investigations into allosteric regulation of Wnt signalling: building the sclerostin franchise

Lead Research Organisation: University of Leicester
Department Name: Molecular and Cell Biology

Abstract

Osteoporosis affects hundreds of millions of people worldwide occurring after a loss of bone strength and integrity. Despite a growing number of patients worldwide current therapeutic options offer limited benefit with the majority inhibiting resorption of bone while having little effect on the restoration of bone that has already been lost. The canonical Wnt signalling pathway has emerged as a key regulator of bone homeostasis with activation of this pathway being tightly regulated by a number of secreted inhibitory proteins such as sclerostin.
Pioneering studies of a range of camelid VHH antibody fragments raised to a cytokine identified previously unknown allosteric sites, where binding of specific VHHs results in modulation of distant functional sites. Determination of structures for VHHs bound to the cytokine identified specific interactions responsible for the allosteric regulation and highlighted the potential to identify synthetic small molecules that would similarly modulate activity.
NMR based studies have shown that sclerostin, like the cytokine, is characterised by regions that show significant flexibility. These flexible regions correspond to sites involved in the interactions between sclerostin and its binding partners. Antibody-assisted structural approaches are likely to identify unknown allosteric sites on sclerostin and/or stabilize key regions required for binding to LRP co-receptors. Function modifying VHHs will be identified and have their structures and interactions characterized. Gaining an understanding of the allosteric potential of sclerostin and how this translates into regulation of protein function will give valuable insights into the mechanism of action of this highly dynamic protein. In addition, further development of antibody-assisted drug discovery technology, together with enhanced understanding of the potential to regulate sclerostin, will assist future identification of small molecules that inhibit sclerostin.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1791043 Studentship BB/M01116X/1 03/10/2016 30/09/2020 Matthew Powell-Grabaskey