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Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success...

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Autores principales: Min, Xiaoshan, Yie, Junming, Wang, Jinghong, Chung, Ben C., Huang, Ching-Shin, Xu, Haoda, Yang, Jie, Deng, Liying, Lin, Joanne, Chen, Qing, Abbott, Christina M., Gundel, Caroline, Thibault, Stephen A., Meng, Tina, Bates, Darren L., Lloyd, David J., Véniant, Murielle M., Wang, Zhulun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973313/
https://www.ncbi.nlm.nih.gov/pubmed/31905038
http://dx.doi.org/10.1080/19420862.2019.1710047
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author Min, Xiaoshan
Yie, Junming
Wang, Jinghong
Chung, Ben C.
Huang, Ching-Shin
Xu, Haoda
Yang, Jie
Deng, Liying
Lin, Joanne
Chen, Qing
Abbott, Christina M.
Gundel, Caroline
Thibault, Stephen A.
Meng, Tina
Bates, Darren L.
Lloyd, David J.
Véniant, Murielle M.
Wang, Zhulun
author_facet Min, Xiaoshan
Yie, Junming
Wang, Jinghong
Chung, Ben C.
Huang, Ching-Shin
Xu, Haoda
Yang, Jie
Deng, Liying
Lin, Joanne
Chen, Qing
Abbott, Christina M.
Gundel, Caroline
Thibault, Stephen A.
Meng, Tina
Bates, Darren L.
Lloyd, David J.
Véniant, Murielle M.
Wang, Zhulun
author_sort Min, Xiaoshan
collection PubMed
description Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success due to lack of effective antagonistic reagents. Previously we reported the discovery of two mouse anti-murine GIPR monoclonal antibodies (mAbs) with distinctive properties in rodent models. Here, we report the detailed structural and biochemical characterization of these two antibodies, mAb1 and mAb2. In vitro and in vivo characterizations demonstrated mAb2 is a full GIPR antagonistic antibody and mAb1 is a non-neutralizing GIPR binder. To understand the molecular basis of these two antibodies, we determined the co-crystal structures of GIPR extracellular domain in complex with mAb1 and with mAb2 at resolutions of 2.1 and 2.6 Å, respectively. While the non-neutralizing mAb1 binds to GIPR without competing with the ligand peptide, mAb2 not only partially occludes the ligand peptide binding, but also recognizes the GIPR C-terminal stalk region in a helical conformation that acts as a molecular mimic of the ligand peptide and locks GIPR in a novel auto-inhibited state. Furthermore, administration of mAb2 in diet-induced obesity mice for 7 weeks leads to both reduction in body weight gain and improvement of metabolic profiles. In contrast, mAb1 has no effect on body weight or other metabolic improvement. Together, our studies reveal the unique molecular mechanism of action underlying the superior antagonistic activity of mAb2 and signify the promising therapeutic potential of effective GIPR antagonism for the treatment of metabolic disorders.
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spelling pubmed-69733132020-01-31 Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor Min, Xiaoshan Yie, Junming Wang, Jinghong Chung, Ben C. Huang, Ching-Shin Xu, Haoda Yang, Jie Deng, Liying Lin, Joanne Chen, Qing Abbott, Christina M. Gundel, Caroline Thibault, Stephen A. Meng, Tina Bates, Darren L. Lloyd, David J. Véniant, Murielle M. Wang, Zhulun MAbs Report Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success due to lack of effective antagonistic reagents. Previously we reported the discovery of two mouse anti-murine GIPR monoclonal antibodies (mAbs) with distinctive properties in rodent models. Here, we report the detailed structural and biochemical characterization of these two antibodies, mAb1 and mAb2. In vitro and in vivo characterizations demonstrated mAb2 is a full GIPR antagonistic antibody and mAb1 is a non-neutralizing GIPR binder. To understand the molecular basis of these two antibodies, we determined the co-crystal structures of GIPR extracellular domain in complex with mAb1 and with mAb2 at resolutions of 2.1 and 2.6 Å, respectively. While the non-neutralizing mAb1 binds to GIPR without competing with the ligand peptide, mAb2 not only partially occludes the ligand peptide binding, but also recognizes the GIPR C-terminal stalk region in a helical conformation that acts as a molecular mimic of the ligand peptide and locks GIPR in a novel auto-inhibited state. Furthermore, administration of mAb2 in diet-induced obesity mice for 7 weeks leads to both reduction in body weight gain and improvement of metabolic profiles. In contrast, mAb1 has no effect on body weight or other metabolic improvement. Together, our studies reveal the unique molecular mechanism of action underlying the superior antagonistic activity of mAb2 and signify the promising therapeutic potential of effective GIPR antagonism for the treatment of metabolic disorders. Taylor & Francis 2020-01-12 /pmc/articles/PMC6973313/ /pubmed/31905038 http://dx.doi.org/10.1080/19420862.2019.1710047 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Report
Min, Xiaoshan
Yie, Junming
Wang, Jinghong
Chung, Ben C.
Huang, Ching-Shin
Xu, Haoda
Yang, Jie
Deng, Liying
Lin, Joanne
Chen, Qing
Abbott, Christina M.
Gundel, Caroline
Thibault, Stephen A.
Meng, Tina
Bates, Darren L.
Lloyd, David J.
Véniant, Murielle M.
Wang, Zhulun
Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
title Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
title_full Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
title_fullStr Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
title_full_unstemmed Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
title_short Molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
title_sort molecular mechanism of an antagonistic antibody against glucose-dependent insulinotropic polypeptide receptor
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973313/
https://www.ncbi.nlm.nih.gov/pubmed/31905038
http://dx.doi.org/10.1080/19420862.2019.1710047
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