Sa Zhining, Zhou Jingqi, Zou Yangyun, Su Zhixi, Gu Xun
State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
Genomics Proteomics Bioinformatics. 2017 Aug;15(4):246-254. doi: 10.1016/j.gpb.2017.03.004. Epub 2017 Jun 20.
Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.
靶向药物的副作用仍然是一个严重问题。一个原因是药物与非预期蛋白质（如旁系同源物）的非选择性结合，这些旁系同源物在序列上高度同源，具有相似的结构和药物结合口袋。为了确定旁系同源物之间可靶向的差异，我们在氨基酸水平分析了已知靶蛋白受体家族G蛋白偶联受体（GPCRs）中两个旁系同源物之间的两种类型（I型和II型）功能差异。胰高血糖素样亚家族中的旁系同源蛋白受体，即胰高血糖素受体（GCGR）和胰高血糖素样肽-1受体（GLP-1R），在配体方面存在差异，并且是2型糖尿病经临床验证的药物靶点。我们的数据表明，II型氨基酸在拮抗剂MK-0893与GCGR的结合位点中显著富集，在GCGR和GLP-1R之间其理化性质发生了根本变化。我们还研究了GCGR和GLP-1R之间I型氨基酸的作用。GCGR和GLP-1R旁系同源物之间的差异特征可能有助于区分它们，从而能够识别结合位点以减少不良副作用并提高药物的靶点特异性。
