Coordination Funds

GTP/GDP交换和GTP结合蛋白固有的GTP酶活性构成了细胞中广泛存在的调控机制。异三聚体αβγG蛋白是G蛋白偶联受体(GPCRs)下游的效应物，它们被用来直接或间接地调节哺乳动物的许多生理过程。尽管G蛋白在近30年前就被发现，并且它们在响应各种细胞外信号时维持体内平衡方面具有相关性，但值得注意的是，很少有人致力于开发选择性和细胞渗透性的药理学药物来抑制这一蛋白家族的成员。这与目前可用于GPCRs药理学控制的调节剂过多形成鲜明对比，可能与抑制受体功能而不是它们共享的信号级联是干扰病理的更具体的方法有关。然而，如果病理很复杂，涉及多个受体及其相关信号回路的失调，就像某些肺部疾病、代谢障碍以及某些形式的疼痛和癌症一样，这种方法可能会失败。因此，开发在完整细胞、分离器官水平上或理想情况下也在活生物体中活跃的G蛋白靶向药物将提供独特的机会来探索更广泛地抑制信号成分所产生的生物学后果。最近，我们的RU将一种著名的G蛋白抑制剂引入科学界：FR900359(FR)。FR900359(FR)是一种大环去脂肽，对G-α-Q、G-α-11和G-α-14蛋白介导的信号转导具有特殊的选择性。它是我们目前RU2372的核心，也是我们组成联盟时唯一可用的GQ特异性抑制剂。鉴于其作为特异性阻断GQ信号的分子探针的突出价值，我们目前的努力目标是：(I)假说驱动的设计和产生新型的、细胞可穿透的、针对不同G蛋白家族的FR支架抑制剂，(Ii)表征其作用机制，包括可视化抑制剂-靶标复合体的原子细节，以及(Iii)应用现有的和新开发的分子在G蛋白异源三聚体、其下游效应器或其上游激活受体的水平上理解信号原理。我们期待这一策略为我们提供对复杂信号网络中单个信号级联在健康和疾病中的相关性和贡献的洞察。

GTP/GDP exchange and the intrinsic GTPase-activity of GTP binding proteins constitute widespread regulatory mechanisms in cells. These are utilized by heterotrimeric αβγ G proteins, downstream effectors of G protein-coupled receptors (GPCRs), to directly or indirectly regulate numerous physiological processes in mammals. Despite the discovery of G proteins almost 30 years ago and their relevance for maintaining homeostasis in response to various extracellular cues, remarkably little effort has been devoted to development of selective and cell permeable pharmacological agents for inhibition of members of this protein family. This is in stark contrast to the plethora of modulators currently available for pharmacological control of GPCRs, and likely relates to the fact that inhibition of receptor function rather than their shared signaling cascades is a more specific approach to interfere with pathologies. Yet, such an approach may fail, if pathology is complex and involves dysregulation of more than one receptor and its associated signaling circuitry as is the case in certain diseases of the lung, in metabolic disturbances, as well as certain forms of pain and cancer. Therefore, development of G protein-targeting pharmacological agents that are active in intact cells, on the level of an isolated organ or ideally also in the living organism would offer unique opportunities to explore the biological consequences that arise from more broad inhibition of signaling components.One such notable G protein inhibiting agent was recently introduced by our RU to the scientific community: FR900359 (FR). FR900359 (FR) is a macrocyclic depsipeptide with exceptional selectivity for inhibition of Gq-mediated signal transduction involving Gαq, Gα11, and Gα14 proteins. It is the core of our current RU2372, and was the only available Gq-specific inhibitor when we formed our consortium. Given its outstanding value as molecular probe to specifically interdict Gq signaling, our current efforts aim at (i) hypothesis-driven design and generation of novel, cell-permeable FR-scaffold-based inhibitors with selectivity for distinct G protein families, (ii) characterization of their mechanism of action including visualization of atomic details of inhibitor-target complexes, and (iii) application of existing and newly developed molecules to understand signaling principles on the level of G protein heterotrimers, their downstream effectors or their upstream activating receptors.We anticipate this strategy to provide us with insight into the relevance and contribution of individual signaling cascades within complex signaling networks in health and disease.