A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification
A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification
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DOI：
10.1038/nchembio.1581
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发表时间：
2014-08-01
影响因子：
14.8
通讯作者：
Carpino, Philip A.
中科院分区：
文献类型：
--
作者：
Nolte, Whitney M.;Fortin, Jean-Philippe;Carpino, Philip A.
我们报道了4-（3-（苄氧基）苯基）-2-乙基亚磺酰基-6-（三氟甲基）嘧啶（BETP），其作为胰高血糖素样肽-1受体（GLP-1 R）的正变构调节剂，共价修饰GLP-1 R中的半胱氨酸347和438。C347位于GLP-1 R的细胞内环3，对BETP和一种结构独特的GLP-1 R前变构调节剂N-（叔丁基）-6，7-二氯-3-（甲磺酰基）喹喔啉-2-胺的活性至关重要。我们进一步表明，胰高血糖素受体中苯丙氨酸345的半胱氨酸取代足以赋予对BETP的敏感性。
We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl) pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.