Contact information
christian.siebold@strubi.ox.ac.uk
Professor Christian Siebold Research Group
Henry Wellcome Building of Genomic Medicine
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(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). |
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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). |
Christian Siebold
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.
Key publications
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Simultaneous binding of Guidance Cues NET1 and RGM blocks extracellular NEO1 signaling.
Journal article
Robinson RA. et al, (2021), Cell, 184, 2103 - 2120.e31
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Structural basis of Smoothened regulation by its extracellular domains
Journal article
Byrne EFX. et al, (2016), Nature, 535, 517 - 522
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The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism.
Journal article
Rudolf AF. et al, (2019), Nature chemical biology, 15, 975 - 982
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Structure of the Repulsive Guidance Molecule (RGM)–Neogenin Signaling Hub
Journal article
Bell CH. et al, (2013), Science, 341, 77 - 80
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Glypicans shield the Wnt lipid moiety to enable signalling at a distance.
Journal article
McGough IJ. et al, (2020), Nature, 585, 85 - 90
Recent publications
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Structure, mechanism, and inhibition of Hedgehog acyltransferase.
Journal article
Coupland CE. et al, (2021), Molecular cell, 81, 5025 - 5038.e10
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Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling
Journal article
Griffiths SC. et al, (2021), Nature Communications, 12
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Patched 1 reduces the accessibility of cholesterol in the outer leaflet of membranes.
Journal article
Kinnebrew M. et al, (2021), eLife, 10
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Relative Affinities of Protein–Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations
Journal article
Ansell TB. et al, (2021), Journal of Chemical Theory and Computation, 17, 6548 - 6558
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Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling
Journal article
Griffiths S. et al, (2021)