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The Role of G Protein-Coupled Receptor in Human Disease
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The Role of G Protein-Coupled Receptor in Human Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 5921

Special Issue Editor

Dr. Xuanmao Jiao

E-Mail Website
Guest Editor
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
Interests: G protein-coupled receptors; G protein; GPCR signaling; GPCR function; human disease; drug development

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) are an integral membrane protein family with the function of transforming extracellular signals to intracellular responses. All GPCRs have very similar structures, with seven transmembrane domains and an extracellular N-terminal, three extracellular loops, three intracellular loops and an intracellular C-terminal. The extracellular N-terminal and loops can bind with ligands and the intracellular C-terminal can bind with G proteins. GPCRs have multiple biological functions and play roles in cardiovascular system functioning, bone development and remodeling, neurotransmitter signaling and autonomic nervous system regulation, senses such as vision, taste and smell, inflammation and immune response, homeostasis maintenance, and tumor growth and metastasis. Either gain or loss of GPCR functions can cause human disease. GPCRs are the largest family of proteins targeted by currently approved drugs. With at least 831 predicted GPCR receptors, no less than 134 are targeted by over 700 FDA/EMA-approved drugs, which account for 35% of approved medicines. This Special Issue will overview the most recent progress in GPCRs and human diseases and provide a commentary of future directions for new drug development to treat human diseases mediated by GPCRs.

Dr. Xuanmao Jiao
Guest Editor

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Keywords

  • G protein-coupled receptors
  • G protein
  • GPCR signaling
  • GPCR function
  • human disease
  • drug development

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Published Papers (2 papers)

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Research

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22 pages, 2860 KiB  
Article
Improving the Modeling of Extracellular Ligand Binding Pockets in RosettaGPCR for Conformational Selection
by Fabian Liessmann, Georg Künze and Jens Meiler
Int. J. Mol. Sci. 2023, 24(9), 7788; https://doi.org/10.3390/ijms24097788 - 24 Apr 2023
Cited by 2 | Viewed by 2375
Abstract
G protein-coupled receptors (GPCRs) are the largest class of drug targets and undergo substantial conformational changes in response to ligand binding. Despite recent progress in GPCR structure determination, static snapshots fail to reflect the conformational space of putative binding pocket geometries to which [...] Read more.
G protein-coupled receptors (GPCRs) are the largest class of drug targets and undergo substantial conformational changes in response to ligand binding. Despite recent progress in GPCR structure determination, static snapshots fail to reflect the conformational space of putative binding pocket geometries to which small molecule ligands can bind. In comparative modeling of GPCRs in the absence of a ligand, often a shrinking of the orthosteric binding pocket is observed. However, the exact prediction of the flexible orthosteric binding site is crucial for adequate structure-based drug discovery. In order to improve ligand docking and guide virtual screening experiments in computer-aided drug discovery, we developed RosettaGPCRPocketSize. The algorithm creates a conformational ensemble of biophysically realistic conformations of the GPCR binding pocket between the TM bundle, which is consistent with a knowledge base of expected pocket geometries. Specifically, tetrahedral volume restraints are defined based on information about critical residues in the orthosteric binding site and their experimentally observed range of Cα-Cα-distances. The output of RosettaGPCRPocketSize is an ensemble of binding pocket geometries that are filtered by energy to ensure biophysically probable arrangements, which can be used for docking simulations. In a benchmark set, pocket shrinkage observed in the default RosettaGPCR was reduced by up to 80% and the binding pocket volume range and geometric diversity were increased. Compared to models from four different GPCR homology model databases (RosettaGPCR, GPCR-Tasser, GPCR-SSFE, and GPCRdb), the here-created models showed more accurate volumes of the orthosteric pocket when evaluated with respect to the crystallographic reference structure. Furthermore, RosettaGPCRPocketSize was able to generate an improved realistic pocket distribution. However, while being superior to other homology models, the accuracy of generated model pockets was comparable to AlphaFold2 models. Furthermore, in a docking benchmark using small-molecule ligands with a higher molecular weight between 400 and 700 Da, a higher success rate in creating native-like binding poses was observed. In summary, RosettaGPCRPocketSize can generate GPCR models with realistic orthosteric pocket volumes, which are useful for structure-based drug discovery applications. Full article
(This article belongs to the Special Issue The Role of G Protein-Coupled Receptor in Human Disease)
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Review

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20 pages, 1308 KiB  
Review
Role of Adhesion G Protein-Coupled Receptors in Immune Dysfunction and Disorder
by Wen-Yi Tseng, Martin Stacey and Hsi-Hsien Lin
Int. J. Mol. Sci. 2023, 24(6), 5499; https://doi.org/10.3390/ijms24065499 - 13 Mar 2023
Cited by 8 | Viewed by 2929
Abstract
Disorders of the immune system, including immunodeficiency, immuno-malignancy, and (auto)inflammatory, autoimmune, and allergic diseases, have a great impact on a host’s health. Cellular communication mediated through cell surface receptors, among different cell types and between cell and microenvironment, plays a critical role in [...] Read more.
Disorders of the immune system, including immunodeficiency, immuno-malignancy, and (auto)inflammatory, autoimmune, and allergic diseases, have a great impact on a host’s health. Cellular communication mediated through cell surface receptors, among different cell types and between cell and microenvironment, plays a critical role in immune responses. Selective members of the adhesion G protein-coupled receptor (aGPCR) family are expressed differentially in diverse immune cell types and have been implicated recently in unique immune dysfunctions and disorders in part due to their dual cell adhesion and signaling roles. Here, we discuss the molecular and functional characteristics of distinctive immune aGPCRs and their physiopathological roles in the immune system. Full article
(This article belongs to the Special Issue The Role of G Protein-Coupled Receptor in Human Disease)
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