Structure, function and drug discovery of GPCR signaling

Abstract

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.

Structural basis of neuropeptide Y signaling through Y1 and Y2 receptors

“…The structural comparison of our two Gi2‐coupled NPY receptors with other class A GPCRs revealed similar conformations. 46 TM6 and TM7 of Y 1 R and Y 2 R adopted nearly identical conformations to the active structures of the neurotensin receptor NTS1, 47 orexin receptors, 35 and the endothelin ET B receptor 33 (Figure S14 ). Furthermore, the structural comparison of two Y 1 R and Y 2 R receptors with the antagonist‐bound NPYRs (PDB ID: 5ZBH, 5ZBQ, and 7DDZ), 31 , 32 supports the contention that these two complexes were in the active state (Figures 6A and D ).…”

MRAP2 Inhibits β-Arrestin-2 Recruitment to the Prokineticin Receptor 2

“…This type of regulator binds an allosteric site that is distinct from the orthosteric site recognised by endogenous ligands and stabilises a specific receptor conformation. The characterisation of the natural allosteric modulation of GPCRs is a promising new approach for GPCR drug discovery compared to classical approaches that focus on the development of small molecules targeting the orthosteric site [51][52][53][54][55][56].…”

Cryo-EM Structure and Biochemical Analysis of the Human Chemokine Receptor CCR8

“…Located on the cell membrane and characterized by seven transmembrane helices, GPCRs are able to mediate signal transduction and take part in many essential physiological activities, thus being promising targets for drug development. − CCR8 is a member of the CCR subfamily of chemokine receptors. It has been a vital drug target in the treatment of cancer immunotherapy as well as autoimmune diseases. − Recently, the structures of human CCR8 in the apo state (3.31 Å) and in complex with an antagonist antibody (Fab1), an endogenous agonist ligand CCL1, and an agonist small molecule LMD-009 have been determined. , In the present study, we also solved the cryo-EM structure of ligand-free CCR8 in complex with G proteins, but with a higher resolution (2.58 Å). Together with previous structural studies of CCR8, , this study will enrich the structural information on CCR8 and, absolutely, will add to the development of CCR8-targeted therapy.…”

“…G protein-coupled receptors (GPCRs), located on the cell membrane, are the largest protein family encoded by the human genome . Activated by chemokines or other ligands, GPCRs play an important role in transducing signals from the extracellular environment to the intracellular environment. − To date, many GPCRs have been identified in humans, and they can be divided into five types according to their amino acid sequences: rhodopsin-like receptors (Class A), secretin receptors (Class B), glutamate receptors (Class C), adhesion receptors (Class D), and frizzled receptors (Class F). , GPCRs have been implicated in a large number of biological events, including the development of cancer and autoimmune diseases, which makes GPCRs perfect drug targets for medicinal drugs. − …”