Targeting adhesion G protein-coupled receptors. Current status and future perspectives

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-11-08 DOI:10.1016/j.str.2024.10.022

Fabian Liessmann, Lukas von Bredow, Jens Meiler, Ines Liebscher

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Abstract

G protein-coupled receptors (GPCRs) orchestrate many physiological functions and are a crucial target in drug discovery. Adhesion GPCRs (aGPCRs), the second largest family within this superfamily, are promising yet underexplored targets for treating various diseases, including obesity, psychiatric disorders, and cancer. However, the receptors’ unique and complex structure and miscellaneous interactions complicate comprehensive pharmacological studies. Despite recent progress in determining structures and elucidation of the activation mechanism, the function of many receptors remains to be determined.This review consolidates current knowledge on aGPCR ligands, focusing on small molecule orthosteric ligands and allosteric modulators identified for the ADGRGs subfamily (subfamily VIII), (GPR56/ADGRG1, GPR64/ADGRG2, GPR97/ADGRG3, GPR114/ADGRG5, GPR126/ADGRG6, and GPR128/ADGRG7). We discuss challenges in hit identification, target validation, and drug discovery, highlighting molecular compositions and recent structural breakthroughs. ADGRG ligands can offer new insights into aGPCR modulation and have significant potential for novel therapeutic interventions targeting various diseases.

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靶向粘附 G 蛋白偶联受体。现状与未来展望

G 蛋白偶联受体（GPCR）协调着许多生理功能，是药物发现的一个重要靶点。粘附 GPCR（aGPCR）是这个超家族中的第二大家族，是治疗肥胖症、精神疾病和癌症等各种疾病的有希望但尚未充分开发的靶点。然而，受体独特而复杂的结构和各种相互作用使全面的药理学研究变得复杂。尽管最近在确定结构和阐明激活机制方面取得了进展，但许多受体的功能仍有待确定。这篇综述整合了当前有关 aGPCR 配体的知识，重点介绍了针对 ADGRGs 亚家族（VIII 亚家族）（GPR56/ADGRG1、GPR64/ADGRG2、GPR97/ADGRG3、GPR114/ADGRG5、GPR126/ADGRG6 和 GPR128/ADGRG7）发现的小分子正交配体和异位调节剂。我们讨论了目标识别、目标验证和药物发现方面的挑战，重点介绍了分子组成和最新的结构突破。ADGRG 配体可为 aGPCR 调控提供新的见解，并具有针对各种疾病的新型治疗干预的巨大潜力。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.