G protein-coupled receptors: structure- and function-based drug discovery

Yang, Dehua; Zhou, Qingtong; Labroska, Viktorija; Qin, Shanshan; Darbalaei, Sanaz; Wu, Yiran; Yuliantie, Elita; Xie, Linshan; Tao, Houchao; Cheng, Jianjun; Liu, Qing; Zhao, Suwen; Wang, Shui; Jiang, Yi; Wang, Mingwei

doi:10.1038/s41392-020-00435-w

Cited by 330 publications

(323 citation statements)

References 324 publications

(466 reference statements)

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“…Combined activation of GLP-1R and GIPR by dual agonists would provide synergistic and improved effects in glycemic and body weight control (41). The GLP-1R/GIPR dual-agonists LY3298176 (developed by Eli Lilly) and NN9709 (developed by Novo Nordisk/Marcadia) as well as GLP-1R/GCGR/GIPR tri-agonist HM15211 (developed by Hamni Pharmaceuticals) are undergoing phase II or III clinical trials (6). The detailed structural information on GIPR reported here will certainly be of value to better understand the mode of actions of these therapeutic peptides.…”

Section: Discussionmentioning

confidence: 96%

“…GIPR, together with GCGR and GLP-1R, form the central endocrine network in regulating insulin sensitivity and energy homeostasis, and they are validated drug targets (3,4,5 ). Intensive efforts were made in drug discovery targeting these receptors (6). A number of GLP-1R selective ligands have been developed successfully to treat type 2 diabetes and obesity.…”

Section: Introductionmentioning

confidence: 99%

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Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

Zhao

Zhang

Zhou

et al. 2021

eLife

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Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a Gs heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C-terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

Zhao

Zhang

Zhou

et al. 2021

eLife

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“…G-protein coupled receptors (GPCRs) alone are targeted by approximately 35% of all approved drugs [ 2 ]. Rational drug discovery pipelines are much more efficient and economical than classical screening approaches but rely heavily on structural data [ 3 ]. However, membrane proteins account for only ~3% of the deposited structures in the PDB [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

A novel high-throughput screen for identifying lipids that stabilise membrane proteins in detergent based solution

et al. 2021

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Membrane proteins have a range of crucial biological functions and are the target of about 60% of all prescribed drugs. For most studies, they need to be extracted out of the lipid-bilayer, e.g. by detergent solubilisation, leading to the loss of native lipids, which may disturb important protein-lipid/bilayer interactions and thus functional and structural integrity. Relipidation of membrane proteins has proven extremely successful for studying challenging targets, but the identification of suitable lipids can be expensive and laborious. Therefore, we developed a screen to aid the high-throughput identification of beneficial lipids. The screen covers a large lipid space and was designed to be suitable for a range of stability assessment methods. Here, we demonstrate its use as a tool for identifying stabilising lipids for three membrane proteins: a bacterial pyrophosphatase (Tm-PPase), a fungal purine transporter (UapA) and a human GPCR (A2AR). A2AR is stabilised by cholesteryl hemisuccinate, a lipid well known to stabilise GPCRs, validating the approach. Additionally, our screen also identified a range of new lipids which stabilised our test proteins, providing a starting point for further investigation and demonstrating its value as a novel tool for membrane protein research. The pre-dispensed screen will be made commercially available to the scientific community in future and has a number of potential applications in the field.

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“…Another group of GPCR ligands has been designed with the goal to treat or prevent diseases that involve, for instance, the cardiovascular, nervous or endocrine systems. In this regard, GPCRs are targets for nearly 35% of the drugs currently in use in clinical practice [ 9 ], and comprise more than 100 types of receptors [ 10 ] divided into six classes according to the following classification [ 11 , 12 ]: rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic adenosine monophosphate (cAMP) receptors (E) and frizzled (F), where classes D and E are not found in vertebrates.…”

Section: Introductionmentioning

confidence: 99%

Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases

et al. 2021

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G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors’ superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the nucleus as an autonomous signaling organelle (triggered by GPCRs). Nuclear GPCRs are involved in physiological (namely cell proliferation, transcription, angiogenesis and survival) and disease processes (cancer, cardiovascular diseases, etc.). In this review we summarize emerging evidence on nuclear GPCRs expression/function (with some nuclear GPCRs evidencing atypical/disruptive signaling pathways) in non-communicable disease, thus, bringing nuclear GPCRs as targets to the forefront of debate.

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G protein-coupled receptors: structure- and function-based drug discovery

Cited by 330 publications

References 324 publications

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

A novel high-throughput screen for identifying lipids that stabilise membrane proteins in detergent based solution

Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases

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