Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

Yang, Dehua; Zhou, Chang; Liu, Qing; Wang, Mingwei

doi:10.1038/aps.2015.78

Cited by 14 publications

(7 citation statements)

References 73 publications

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“…Class B1 GPCRs are traditionally considered difficult targets for small, drug-like molecules ( 296 ). In particular, the orthosteric sites that peptide ligands engage are expansive and shallow, which introduces challenges akin to those of targeting protein–protein interfaces with small molecules ( 297 ).…”

Section: Nonpeptide Ligand Bindingmentioning

confidence: 99%

New Insights into the Structure and Function of Class B1 GPCRs

et al. 2022

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G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily of 15 receptors that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. Class B1 GPCRs are critical regulators of homeostasis, and as such, many are important drug targets. While most transmembrane proteins, including GPCRs, are recalcitrant to crystallization, recent advances in electron cryo-microscopy (cryo-EM) have facilitated a rapid expansion of the structural understanding of membrane proteins. As a testament to this success, structures for all the class B1 receptors bound to G proteins have been determined by cryo-EM in the past five years. Further advances in cryo-EM have uncovered dynamics of these receptors, ligands, and signalling partners. Here, we examine the recent structural underpinnings of the class B1 GPCRs with an emphasis on structure-function relationships.

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Section: Nonpeptide Ligand Bindingmentioning

confidence: 99%

New Insights into the Structure and Function of Class B1 GPCRs

et al. 2022

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“…We have finally entered an era in which small-molecule nonpeptidic GLP-1R agonists are now available ( Fig. 7 ), although it still poses a tremendous challenge to make them adequately potent and bioavailable ( Yang et al, 2015a ). Most of these are thought to act within the helical bundle of GLP-1R.…”

Section: Pharmaceutical Development and Therapeuticsmentioning

confidence: 99%

Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

Graaf

Donnelly

Wootten³

et al. 2016

Pharmacol Rev

Self Cite

281

295

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The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.

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“…Glucagon, a 29 amino acid peptide, is released from the α-cells of the islets of Langerhans located in the pancreas and is an endogenous agonist for glucagon receptor (GCGR) . Glucagon binding to GCGR stimulates hepatic glucose production through gluconeogenesis and glycogenolysis, thus increasing hepatic glucose production. , GCGR is expressed in liver, intestinal smooth muscle, kidney, brain, and adipose tissue . The antagonism of GCGR provides a promising strategy for the potential treatment of type 2 diabetes mellitus, considering its significant role in the regulation of plasma glucose levels. − …”

Section: Class B Allosteric Gpcr–small-molecule Modulator Interactionsmentioning

confidence: 99%

Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions

2018

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G-protein-coupled receptors (GPCRs) are the largest class of signaling receptors that are most frequently targeted by therapeutic drugs. Allosteric modulators bound to GPCRs at allosteric sites provide the potential for differential selectivity and improved safety compared with traditional orthosteric ligands. The recent breakthroughs in GPCR structural biology have made structures of GPCRs from classes A, B, C, and F complexed with small-molecule allosteric modulators available. Knowledge of the detailed receptor-modulator interactions at the allosteric sites is useful for structure-based GPCR drug design of novel therapeutics. This Perspective comprehensively summarizes the current status of structural complexes between GPCRs and their small-molecule allosteric modulators, particularly the key receptor-modulator interactions at the allosteric sites. Then, the structural diversity of allosteric sites across four GPCR subfamilies is compared. This study is expected to contribute to the design of GPCR allosteric drugs with an improved therapeutic action.

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Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure

Cited by 14 publications

References 73 publications

New Insights into the Structure and Function of Class B1 GPCRs

New Insights into the Structure and Function of Class B1 GPCRs

Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes

Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions

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