4QIN
Structure of the human smoothened receptor in complex with SAG1.5
Summary for 4QIN
| Entry DOI | 10.2210/pdb4qin/pdb |
| Related | 4O9R 4QIM |
| Descriptor | Smoothened homolog/Soluble cytochrome b562 chimeric protein, 3-chloro-4,7-difluoro-N-[trans-4-(methylamino)cyclohexyl]-N-[3-(pyridin-4-yl)benzyl]-1-benzothiophene-2-carboxamide (3 entities in total) |
| Functional Keywords | human smoothened receptor, agonist, novel protein engineering, gpcr network, membrane protein, psi-biology, structural genomics, gpcr, membrane, signaling protein |
| Biological source | Homo sapiens More |
| Cellular location | Membrane ; Multi-pass membrane protein : Q99835 |
| Total number of polymer chains | 1 |
| Total formula weight | 52921.24 |
| Authors | Wang, C.,Wu, H.,Evron, T.,Vardy, E.,Han, G.W.,Huang, X.-P.,Hufeisen, S.J.,Mangano, T.J.,Urban, D.J.,Katritch, V.,Cherezov, V.,Caron, M.G.,Roth, B.L.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2014-05-31, release date: 2014-07-23, Last modification date: 2024-11-20) |
| Primary citation | Wang, C.,Wu, H.,Evron, T.,Vardy, E.,Han, G.W.,Huang, X.P.,Hufeisen, S.J.,Mangano, T.J.,Urban, D.J.,Katritch, V.,Cherezov, V.,Caron, M.G.,Roth, B.L.,Stevens, R.C. Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun, 5:4355-4355, 2014 Cited by PubMed Abstract: The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules. PubMed: 25008467DOI: 10.1038/ncomms5355 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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