6D32
Crystal structure of Xenopus Smoothened in complex with cyclopamine
Summary for 6D32
| Entry DOI | 10.2210/pdb6d32/pdb |
| Descriptor | Smoothened,Soluble cytochrome b562,Smoothened, Cyclopamine (2 entities in total) |
| Functional Keywords | gpcr, hedgehog signaling, class frizzled, sterol, membrane protein |
| Biological source | Xenopus laevis (African clawed frog) More |
| Total number of polymer chains | 1 |
| Total formula weight | 69807.54 |
| Authors | Huang, P.,Zheng, S.,Kim, Y.,Kruse, A.C.,Salic, A. (deposition date: 2018-04-14, release date: 2018-05-23, Last modification date: 2023-10-04) |
| Primary citation | Huang, P.,Zheng, S.,Wierbowski, B.M.,Kim, Y.,Nedelcu, D.,Aravena, L.,Liu, J.,Kruse, A.C.,Salic, A. Structural Basis of Smoothened Activation in Hedgehog Signaling. Cell, 174:312-324.e16, 2018 Cited by PubMed Abstract: The seven-transmembrane-spanning protein Smoothened is the central transducer in Hedgehog signaling, a pathway fundamental in development and in cancer. Smoothened is activated by cholesterol binding to its extracellular cysteine-rich domain (CRD). How this interaction leads to changes in the transmembrane domain and Smoothened activation is unknown. Here, we report crystal structures of sterol-activated Smoothened. The CRD undergoes a dramatic reorientation, allosterically causing the transmembrane domain to adopt a conformation similar to active G-protein-coupled receptors. We show that Smoothened contains a unique inhibitory π-cation lock, which is broken on activation and is disrupted in constitutively active oncogenic mutants. Smoothened activation opens a hydrophobic tunnel, suggesting a pathway for cholesterol movement from the inner membrane leaflet to the CRD. All Smoothened antagonists bind the transmembrane domain and block tunnel opening, but cyclopamine also binds the CRD, inducing the active transmembrane conformation. Together, these results define the mechanisms of Smoothened activation and inhibition. PubMed: 29804838DOI: 10.1016/j.cell.2018.04.029 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.751 Å) |
Structure validation
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