4QIN

Structure of the human smoothened receptor in complex with SAG1.5

4QIN の概要

• エントリーDOI: 10.2210/pdb4qin/pdb
• 関連するPDBエントリー: 4O9R 4QIM
• 分子名称: 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)
• 機能のキーワード: human smoothened receptor, agonist, novel protein engineering, gpcr network, membrane protein, psi-biology, structural genomics, gpcr, membrane, signaling protein
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Membrane ; Multi-pass membrane protein : Q99835
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52921.24

構造登録者

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) (登録日: 2014-05-31, 公開日: 2014-07-23, 最終更新日: 2024-11-20)

主引用文献

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

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: 25008467
DOI: 10.1038/ncomms5355

実験手法

X-RAY DIFFRACTION (2.6 Å)