Borah Madhurjya Protim, Trakroo Deepika, Soni Neeraj, Kumari Punita, Baidya Mithu
Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, Jammu and Kashmir 181221, India.
Indian Institute of Science Education and Research Bhopal (IISERB), Department of Biological Sciences, Bhopal, Madhya Pradesh 462066, India.
Biochemistry. 2025 Jan 7;64(1):1-14. doi: 10.1021/acs.biochem.4c00676. Epub 2024 Nov 29.
G protein-coupled receptors (GPCRs) play a pivotal role in regulating numerous physiological processes through their interactions with two key effectors: G proteins and β-arrestins (βarrs). This makes them crucial targets for therapeutic drug development. Interestingly, the evolving concept of biased signaling where ligands selectively activate either the G proteins or the βarrs has not only refined our understanding of segregation of physiological responses downstream of GPCRs but has also revolutionized drug discovery, offering the potential for treatments with enhanced efficacy and minimal side effects. This Review explores the mechanisms behind biased agonism, exploring it through various lenses, including ligand, receptor, cellular systems, location, and tissue-specific biases. It also offers structural insights into both orthosteric and allosteric ligand-binding pockets, structural rearrangements associated with the loops, and how ligand-engineering can contribute to biased signaling. Moreover, we also discuss the unique conformational signature in an intrinsically biased GPCR, which currently remains relatively less explored and adds a new dimension in biased signaling. Lastly, we address the translational challenges and practical considerations in characterizing bias, emphasizing its therapeutic potential and the latest advancements in drug development. By designing ligands that target specific signaling pathways, biased signaling presents a transformative approach to creating safer and more effective therapies. This Review focuses on our current understanding of GPCR-biased signaling, discussing potential mechanisms that lead to bias, the effect of bias on GPCR structures at a molecular level, recent advancements, and its profound potential to drive innovation in drug discovery.
G蛋白偶联受体（GPCRs）通过与两种关键效应器——G蛋白和β-抑制蛋白（βarrs）相互作用，在调节众多生理过程中发挥着关键作用。这使它们成为治疗药物开发的关键靶点。有趣的是，偏向性信号传导这一不断发展的概念，即配体选择性激活G蛋白或βarrs，不仅完善了我们对GPCR下游生理反应分离的理解，还彻底改变了药物发现，为开发疗效增强且副作用最小的治疗方法提供了潜力。本综述探讨了偏向性激动背后的机制，从多个角度进行研究，包括配体、受体、细胞系统、位置和组织特异性偏向。它还提供了关于正构和别构配体结合口袋的结构见解、与环相关的结构重排，以及配体工程如何有助于偏向性信号传导。此外，我们还讨论了内在偏向性GPCR中独特的构象特征，目前对其研究相对较少，它为偏向性信号传导增添了新的维度。最后，我们阐述了在表征偏向性时的转化挑战和实际考虑因素，强调其治疗潜力和药物开发的最新进展。通过设计靶向特定信号通路的配体，偏向性信号传导为创造更安全、更有效的治疗方法提供了一种变革性方法。本综述重点关注我们目前对GPCR偏向性信号传导的理解，讨论导致偏向性的潜在机制、偏向性在分子水平对GPCR结构的影响、最新进展，以及其在推动药物发现创新方面的巨大潜力。
