SFB 1423: Structural Dynamics of GPCR Activation and Signaling

G蛋白偶联受体（GPCRs）是一种在真核生物几乎所有生理功能中发挥核心作用的膜受体。它们结合多种激动剂，这种结合引起构象变化，触发不同细胞内蛋白质的激活，如G蛋白和抑制蛋白。GPCR是非常有吸引力的药物靶标，我们目前的结构理解使得合理的药物设计和开发具有挑战性，但越来越可行。然而，GPCR、它们的配体和细胞内信号分子之间的相互作用比以前预期的更复杂。GPCR具有高度动态的结构，其以多种不同的构象状态存在，其功能性质不同。这些状态由空间和时间上定义的分子-分子相互作用决定，使得GPCR信号非常复杂。 CRC旨在阐明与GPCR功能相关的各种激活状态的结构标志。一个广泛的方法将协同应用：计算技术，结构方法，定点诱变，交联和质谱（MS），以及功能细胞为基础的分析。肽GPCR和aGPCR的结构动力学将与充分表征的受体的结构动力学进行比较，以确定共同的原理以及受体组和类别之间的差异。信号动力学和蛋白酶激活受体的新方面将包括在内。然而，GPCR激活的结构动力学以及受体激活和信号选择性的调节是所有项目的核心问题。总的来说，我们的目标是回答以下问题：我们如何才能把在第一个融资期通过结构分析获得的快照转化为GPCR激活和信号传导动态过程的一致画面？不同类型的配体如何影响GPCR的动力学和运输，以及与不同效应蛋白的相互作用？细胞外和细胞内信号传导和偶联机制是如何相互作用的？我们如何利用结构动力学的知识来获得信号蛋白的谱并预测配体及其活性？

G protein-coupled receptors (GPCRs) are membrane receptors that play a central role in nearly all physiological functions of eukaryotic organisms. They bind a wide variety of agonists, and this binding causes conformational changes triggering activation of different intracellular proteins, such as G proteins and arrestins. GPCRs are highly attractive drug targets, and our current structural understanding makes a rational drug de-sign and development challenging, but increasingly feasible. However, the interplay between GPCRs, their ligands and intracellular signaling molecules is more complex than previously anticipated. GPCRs feature highly dynamic structures which exist in multiple different conformational states differing in their functional properties. These states are determined by spatially and temporally defined molecule-molecule interactions making GPCR signaling very complex. The CRC aims to elucidate structural hallmarks in various states of activation, which are linked to GPCR function. A broad spectrum of methods will be applied synergistically: computational techniques, structural methods, site-directed mutagenesis, crosslinking and mass spectrometry (MS), as well as functional cell-based analyses. The structural dynamics of peptide GPCRs and aGPCRs will be compared to those of the well-characterized receptors to identify common principles but also differences between receptor groups and classes. Novel aspects of signaling dynamics and protease-activated receptors will be included. Structural dynamics of GPCR activation and the modulation of receptor activation and signal selectivity, however, is the central question of all projects. Overall, we aim to answer the following questions: How can we turn snapshots obtained by structural analyses in the first funding period into a consistent picture of the dynamic processes of GPCR activation and signaling? How do different types of ligands affect the dynamics and trafficking of GPCRs, and the interaction with different effector proteins? How is the interplay of extracellular and intracellular signaling and coupling mechanism orchestrated? How can we use the knowledge of the structural dynamics to obtain signaling protein profiles and to predict ligands and their activity?