Structural Basis of Smoothened Activation in Hedgehog Signaling.
Structural Basis of Smoothened Activation in Hedgehog Signaling.
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DOI：
10.1016/j.cell.2018.04.029
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发表时间：
2018-07-12
期刊：
影响因子：
64.5
通讯作者：
Salic A
中科院分区：
文献类型：
--
作者：
Huang P;Zheng S;Wierbowski BM;Kim Y;Nedelcu D;Aravena L;Liu J;Kruse AC;Salic A
七跨膜蛋白Smoothened是Hedgehog信号传导的中心转换器，Hedgehog信号传导是发育和癌症的基本途径。Smoothened通过胆固醇与其细胞外富含半胱氨酸结构域（CRD）结合而激活。这种相互作用如何导致跨膜结构域的变化和Smoothened激活尚不清楚。在这里，我们报告晶体结构的甾醇激活平滑。CRD经历了戏剧性的重新定位，变构导致跨膜结构域采取类似于活性G蛋白偶联受体的构象。我们发现Smoothened含有一个独特的抑制性π-阳离子锁，它在激活时被打破，并在组成型活性致癌突变体中被破坏。平滑的激活打开了疏水通道，表明胆固醇从内膜瓣叶移动到CRD的途径。所有Smoothened拮抗剂结合跨膜结构域并阻断隧道开放，但环巴胺也结合CRD，诱导活性跨膜构象。总之，这些结果定义了Smoothened激活和抑制的机制。甾醇结合的Smoothened分子的晶体结构揭示了使人想起其他类别的G蛋白偶联受体的活性构象。
The seven transmembrane-spanning protein Smoothened is the central transducer in Hedgehog signaling, a pathway fundamental in development and 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 upon 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 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. Crystal structures of sterol-bound Smoothened molecules reveal active conformations reminiscent of other classes of G protein-coupled receptors.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.8
作者：
Choe, Hui-Woog;Kim, Yong Ju;Ernst, Oliver P.
通讯作者：
Ernst, Oliver P.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Corbit, KC;Aanstad, P;Reiter, JF
通讯作者：
Reiter, JF