A sphingosine 1-phosphate receptor 2 selective allosteric agonist.
A sphingosine 1-phosphate receptor 2 selective allosteric agonist.
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1-磷酸受体2选择性变构激动剂。
DOI：
10.1016/j.bmc.2013.06.012
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Brown SJ
中科院分区：
文献类型：
--
作者：
Satsu H;Schaeffer MT;Guerrero M;Saldana A;Eberhart C;Hodder P;Cayanan C;Schürer S;Bhhatarai B;Roberts E;Rosen H;Brown SJ
鞘氨醇1-磷酸受体2（S1PR2）的分子探针工具化合物对于研究涉及S1PR2受体的多种生物过程是重要的。其中包括NF-κ B介导的肿瘤细胞存活和成纤维细胞对纤连蛋白的趋化性。在这里，我们报告我们的努力，以确定选择性化学探针S1PR2和他们的表征。我们采用高通量筛选来鉴定两种激活S1PR2受体的化合物。SAR优化导致具有高纳摩尔效力的化合物。这些化合物XAX-162和CYM-5520具有高度选择性，不会激活其他S1P受体。CYM-5520与拮抗剂JTE-013的结合不具有竞争性。负责与1-磷酸鞘氨醇（S1P）的两性离子头基结合的受体残基的突变消除了S1P对受体的激活，但不消除CYM-5520对受体的激活。与放射性标记的S1P的竞争性结合实验表明，CYM-5520是一种变构激动剂，不取代天然配体。计算建模表明，CYM-5520在正构结合口袋中结合较低，并且与S1P的共结合在能量上耐受良好。总之，我们已经鉴定了变构S1PR2选择性激动剂化合物。
Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound.
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影响因子：
4
作者：
Jo, Euijung;Bhhatarai, Barun;Repetto, Emanuela;Guerrero, Miguel;Riley, Sean;Brown, Steven J.;Kohno, Yasushi;Roberts, Edward;Schuerer, Stephan C.;Rosen, Hugh
通讯作者：
Rosen, Hugh
影响因子：
15.9
作者：
Skoura, Athanasia;Sanchez, Teresa;Hla, Timothy
通讯作者：
Hla, Timothy
影响因子：
3.3
作者：
Kim, Kyeok;Kim, Yu-Lee;Im, Dong-Soon
通讯作者：
Im, Dong-Soon
影响因子：
--
作者：
Blom T;Bergelin N;Meinander A;Löf C;Slotte JP;Eriksson JE;Törnquist K
通讯作者：
Törnquist K
影响因子：
14.8
作者：
Sanna, M. Germana;Wang, Sheng-Kai;Rosen, Hugh
通讯作者：
Rosen, Hugh