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Engineering therapeutic antibodies targeting G-protein–coupled receptors

1 , 1 , *

Experimental & Molecular Medicine

Nature Publishing Group

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      Abstract

      G-protein–coupled receptors (GPCRs) are one of the most attractive therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of therapeutic anti-GPCR antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution.

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      Most cited references 60

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        Crystal structure of rhodopsin: A G protein-coupled receptor.

        Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane alpha helices connected by six loops of varying lengths. We determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the seven-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G-protein activation occurs, also suggests a possible structural change upon photoactivation.
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          The structure and function of G-protein-coupled receptors.

          G-protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants, and so have great potential as therapeutic targets for a broad spectrum of diseases. They are also fascinating molecules from the perspective of membrane-protein structure and biology. Great progress has been made over the past three decades in understanding diverse GPCRs, from pharmacology to functional characterization in vivo. Recent high-resolution structural studies have provided insights into the molecular mechanisms of GPCR activation and constitutive activity.
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            Author and article information

            Affiliations
            [1 ]Department of Bio and Nano Chemistry, Kookmin University , Seoul, Korea
            Author notes
            [* ]Department of Bio and Nano Chemistry, Kookmin University , Seoul 136-702, Korea. E-mail: sjung@ 123456kookmin.ac.kr
            Journal
            Exp Mol Med
            Exp. Mol. Med
            Experimental & Molecular Medicine
            Nature Publishing Group
            1226-3613
            2092-6413
            February 2016
            05 February 2016
            1 February 2016
            : 48
            : 2
            : e207
            26846450
            4892866
            emm2015105
            10.1038/emm.2015.105
            Copyright © 2016 KSBMB.

            This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

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            Molecular medicine

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