Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
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Anaphase bridges in fission yeast cells
Whitby lab
Lactose permease represented using bending cylinders in Bendix software
Caroline Dahl, Sansom lab
Epithelial cells in C. elegans showing a seam cell that failed to undergo cytokinesis
Serena Ding, Woollard lab
Collage of Drosophila third instar larva optic lobe
Lu Yang, Davis lab
First year Biochemistry students at a practical class
Image showing the global movement of lipids in a model planar membrane
Matthieu Chavent, Sansom lab
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Smoothly does it: Structural insights into an unusual G-protein coupled receptor

Smoothened receptor

Crystal Structure of human Smoothened receptor embedded in a lipid bilayer (George Hedger)

A collaborative project between the Newstead and Sansom groups in the Department of Biochemistry and Christian Siebold’s group in the Division of Structural Biology has led to the first high resolution structure of a full length G-Protein Coupled Receptor called Smoothened. 

Smoothened plays an essential role in the Hedgehog signaling pathway which is a key regulator of tissue and limb development in animals. Smoothened signals through a complex network of protein-protein interactions in the cytoplasm to activate a series of genes that control how our bodies grow. It is also the target of a widely used anti-cancer drug, used in the treatment of basal-cell carcinoma.

The research published in Nature (1) reveals for the first time how the extra-cellular ligand binding cysteine-rich domain docks above the canonical hepta helical receptor domain. 

The structure also reveals many new and exciting insights into the regulation of this key developmental receptor. Most notable was the discovery that cholesterol binds to the extra-cellular domain. In the absence of cholesterol, the cysteine-rich domain possesses a degree of conformational flexibility, while cholesterol binding stabilizes this domain via key interactions. Experiments carried out in a mouse knock out model by Rajat Rohatgi in the Department of Biochemistry and Medicine, Stanford, USA show that cholesterol binding has an important and unexpected role in switching off the receptor during development.  

The current study also reports the structure of Smoothened bound to the anti- cancer drug vismodegib, which shows that drug and cholesterol bind to different sites. These new insights may lead to new routes for drug development.

Professor Newstead comments that this breakthrough was made possible through the generous support of the EPA Cephalosporin fund, which allowed the purchase of the Lipid Cubic Phase crystallization robot for the Crystallisation Facility within the Department of Biochemistry and that has allowed our continued success in membrane protein structural biology. 

(1) Structural basis of Smoothened regulation by its extracellular domains. Eamon F.X. Byrne, Ria Sircar, Paul Miller, George Hedger, Sigrid Nachtergaele, Giovanni Luchetti, Mark S. P. Sansom, Simon Newstead, Rajat Rohatgi, Christian Siebold. Nature, 2016 Jul 20;535(7613):517-522.







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