(A) Repulsive Guidance Molecule (RGM) in complex with its receptor NEO1 (Science 2013, Cell 2021). (B) RGM-NEO1-BMP complex, revealing that RGM bridges the NEO1 and BMP morphogen pathways (NSMB 2015).
|Structures of the GPCR and Hh signal transducer Smoothened bound its agonist cholesterol and the anti-cancer drug vismodegib, respectively (Nature 2016, ELife 2016, Nature Chem Biol 2019).|
Professor of Structural Biology
Structural studies on Morphogen Signalling
A handful of secreted morphogen signalling molecules, acting in a spatial and gradient-dependent manner, orchestrate the development of multicellular organism. Morphogen dysfunction leads to a range of diseases and defects in adult stem cell populations. Their importance in human disease has become increasingly clear over the past decade: dysfunctions of the pathways are known to lead to severe developmental and neurological diseases, and cancer.
Our group seeks to generate mechanistic insights relevant to disease and embryonic development focusing on two fundamental morphogen signalling systems: the Hedgehog (Hh) and the bone morphogenetic protein (BMP) pathways. Extracellular Hh and BMP signals are mediated by various cell surface receptor molecules. We aim to unravel the molecular mechanisms underlying Hh and BMP morphogen gradient formation and signal transduction across the cell membrane.
To achieve this, we are using structural biology techniques such as X-ray crystallography and cryo electron microscopy to obtain molecular snapshots of Hh and BMP interactions with other proteins. We combine atomic details from in vitro structural and biophysical studies on single molecules with analyses of Hh and BMP function in living cells. Our findings will be integrated with those from developmental and cellular biologists to provide a deeper understanding of these pathways and explore translational opportunities, for example in anti-cancer therapy.
Patched 1 regulates Smoothened by controlling sterol binding to its extracellular cysteine-rich domain.
Kinnebrew M. et al, (2022), Science advances, 8
Structure, mechanism, and inhibition of Hedgehog acyltransferase.
Coupland CE. et al, (2021), Molecular cell, 81, 5025 - 5038.e10
Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling
Griffiths SC. et al, (2021), Nature Communications, 12
Patched 1 reduces the accessibility of cholesterol in the outer leaflet of membranes.
Kinnebrew M. et al, (2021), eLife, 10
Relative Affinities of Protein–Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations
Ansell TB. et al, (2021), Journal of Chemical Theory and Computation, 17, 6548 - 6558