Functional Determinants in G-Protein-Coupled Receptors

G蛋白偶联受体的功能性拮抗剂 项目总结/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， 希望在这个跨膜受体和药物的主要家族中开发新的治疗方法， 目标的我们的假设是，进化趋异模式可以揭示GPCR序列的作用， 位置单独或一起发挥作用，以介导配体结合，变构构象转换， 以及最后传出信号通路的配体偏向性激活，其可以是G蛋白依赖性的或 独立的在过去的资助期间，对这种进化模式的计算分析揭示了： 多巴胺D2 R受体跨膜区的分子内变构通讯;模块 控制B2 AR功能选择性的变构开关的组分;一种新的非经典cAMP- 相同受体中独立信号传导途径;和细胞外 代谢型谷氨酸受体（MGluR）。技术进步导致：提高了评估的准确性 蛋白质编码突变的影响，通过第一原理方程的进化变异， 基因型和表型;我们对进化趋异分析的推广，以考虑协变 残留物;和新的方法来解开复杂的同时测定读数，以分层药物对 GPCR。这些数据和其他数据一起支持了联合收割机结合生物学和算法目标的新目标：到 突变滴定生物胺受体的信号偏差。2.揭示代谢性疾病中的变构介质 谷氨酸受体3.确定GPCR突变在癌症中的系统作用。其成果应当 揭示了一个重要的药物靶标家族中信号传导的分子基础的新方面。它将 还将序列和结构基因组学数据库与功能的分子基础和合理的重建联系起来， 设计蛋白质功能-操纵细胞途径的关键步骤。

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.