Functional Determinants in G-Protein-Coupled Receptors

G蛋白偶联受体的功能决定因素 项目摘要/摘要 这项工作的长期目标是合理地操纵G蛋白偶联受体(GPCRs)的激活 希望在这一主要的跨膜受体和药物家族中开发新的治疗方法 目标。我们的假设是，进化分化模式可以揭示GPCR序列的作用 位置单独或共同发挥作用，以调节配体结合、变构构象转换， 最后，配体偏向激活传出信号通路，这可以是G蛋白依赖的或 独立自主。在过去的筹资期间，对这些演变模式的计算分析显示： 多巴胺D2R受体跨膜区的分子内变构通讯 控制B2AR功能选择性的变构开关的组成；一种新的非正则cAMP- 同一受体中独立信号通路；以及细胞外的配基特异性决定因素 代谢性谷氨酸受体结构域(MGluR)。技术进步导致：评估的准确性提高 通过第一原理方程研究编码突变对蛋白质进化变异的影响 基因型和表型；我们对进化差异的分析的概括，以考虑协变 以及解开复杂的同时分析读数以分层药物作用的新方法 GPCRs。这些数据和其他数据一起支持结合生物学和算法目标的新目标：1. 突变滴定生物胺受体的信号偏向。2.发现新陈代谢中的变构介质 谷氨酸受体。3.确定GPCR突变在癌症中的系统性作用。结果应该是 揭示在一个重要的药物靶标家族中信号的分子基础的新方面。会的 还将序列和结构基因组学数据库与功能的分子基础和有理Re-Re联系起来。 蛋白质功能的设计--操纵细胞通路的关键步骤。

FUNCTIONAL DETERMINANTS OF G PROTEIN-COUPLED RECEPTORS PROJECT SUMMARY/ABSTRACT The long-term goal of this work is to rationally manipulate G protein-coupled receptor (GPCRs) activation with the hope to develop novel therapeutic approaches in this major family of transmembrane receptors and drug targets. Our hypothesis is that evolutionary divergence patterns can reveal the roles that GPCR sequence positions play, individually or together, in order to mediate ligand binding, allosteric conformational switching, and finally ligand-biased activation of efferent signaling pathways, which can be G protein-dependent or independent. In the past funding period, computational analysis of such evolutionary patterns revealed: Intramolecular allosteric communication in the transmembrane domain of dopamine D2R receptor; Modular components of an allosteric switch controlling B2AR functional selectivity; A new non-canonical cAMP- independent signaling pathway in that same receptor; and Ligand specificity determinants in the extracellular domain of metabotropic glutamate receptors (MGluR). Technical progress led to: increased accuracy to assess the impact of coding mutations in proteins through a first-principle equation for the evolutionary variations of genotype and phenotype; The generalization of our analyses of evolutionary divergence to consider co-varying residues; and new methods to unravel complex simultaneous assay readouts to stratify drug effects on GPCRs. Together these and other data support new aims that combine biological and algorithmic goals: 1. To titrate mutationally the signaling bias of bioamine receptors. 2. To uncover allosteric mediators in metabotropic glutamate receptors. 3. To identify a systematic role of GPCR mutations in cancer. The outcome should reveal new aspects of the molecular basis of signaling in an important family of pharmaceutical targets. It will also link sequence and structure genomics databases to the molecular basis of function and to the rational re- design of protein function–key steps towards manipulating cellular pathways.