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Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors
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Zeitschriftentitel: | Pharmacology Research & Perspectives |
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Personen und Körperschaften: | , , , , , , , , , , |
In: | Pharmacology Research & Perspectives, 7, 2019, 1 |
Format: | E-Article |
Sprache: | Englisch |
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Wiley
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author_facet |
Wang, Lien Lee, Grace Shih, Amy Kuei, Chester Nepomuceno, Diane Wennerholm, Michelle Fan, Frances Wu, Jiejun Bonaventure, Pascal Lovenberg, Timothy W. Liu, Changlu Wang, Lien Lee, Grace Shih, Amy Kuei, Chester Nepomuceno, Diane Wennerholm, Michelle Fan, Frances Wu, Jiejun Bonaventure, Pascal Lovenberg, Timothy W. Liu, Changlu |
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author |
Wang, Lien Lee, Grace Shih, Amy Kuei, Chester Nepomuceno, Diane Wennerholm, Michelle Fan, Frances Wu, Jiejun Bonaventure, Pascal Lovenberg, Timothy W. Liu, Changlu |
spellingShingle |
Wang, Lien Lee, Grace Shih, Amy Kuei, Chester Nepomuceno, Diane Wennerholm, Michelle Fan, Frances Wu, Jiejun Bonaventure, Pascal Lovenberg, Timothy W. Liu, Changlu Pharmacology Research & Perspectives Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors General Pharmacology, Toxicology and Pharmaceutics Neurology |
author_sort |
wang, lien |
spelling |
Wang, Lien Lee, Grace Shih, Amy Kuei, Chester Nepomuceno, Diane Wennerholm, Michelle Fan, Frances Wu, Jiejun Bonaventure, Pascal Lovenberg, Timothy W. Liu, Changlu 2052-1707 2052-1707 Wiley General Pharmacology, Toxicology and Pharmaceutics Neurology http://dx.doi.org/10.1002/prp2.466 <jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">GPR</jats:styled-content>139 is a Gq‐coupled receptor activated by the essential amino acids L‐tryptophan (L‐Trp) and L‐phenylalanine (L‐Phe). We carried out mutagenesis studies of the human <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 receptor to identify the critical structural motifs required for <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 activation. We applied site‐directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 clones with gain‐of‐function, reduction‐of‐function or loss‐of‐function mutations. The agonist pharmacology of these mutant receptors was characterized and compared to wild‐type receptor using calcium mobilization, radioligand binding, and protein expression assays. The structure‐activity data were incorporated into a homology model which highlights that many of the gain‐of‐function mutations are either in or immediately adjacent to the purported orthosteric ligand binding site, whereas the loss‐of‐function mutations were largely in the intracellular G‐protein binding area or were disrupters of the helix integrity. There were also some reduction‐of‐function mutations in the orthosteric ligand binding site. These findings may not only facilitate the rational design of novel agonists and antagonists of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139, but also may guide the design of transgenic animal models to study the physiological function of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139.</jats:p> Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors Pharmacology Research & Perspectives |
doi_str_mv |
10.1002/prp2.466 |
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title |
Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_unstemmed |
Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_full |
Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_fullStr |
Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_full_unstemmed |
Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_short |
Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_sort |
mutagenesis of gpr139 reveals ways to create gain or loss of function receptors |
topic |
General Pharmacology, Toxicology and Pharmaceutics Neurology |
url |
http://dx.doi.org/10.1002/prp2.466 |
publishDate |
2019 |
physical |
|
description |
<jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">GPR</jats:styled-content>139 is a Gq‐coupled receptor activated by the essential amino acids L‐tryptophan (L‐Trp) and L‐phenylalanine (L‐Phe). We carried out mutagenesis studies of the human <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 receptor to identify the critical structural motifs required for <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 activation. We applied site‐directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 clones with gain‐of‐function, reduction‐of‐function or loss‐of‐function mutations. The agonist pharmacology of these mutant receptors was characterized and compared to wild‐type receptor using calcium mobilization, radioligand binding, and protein expression assays. The structure‐activity data were incorporated into a homology model which highlights that many of the gain‐of‐function mutations are either in or immediately adjacent to the purported orthosteric ligand binding site, whereas the loss‐of‐function mutations were largely in the intracellular G‐protein binding area or were disrupters of the helix integrity. There were also some reduction‐of‐function mutations in the orthosteric ligand binding site. These findings may not only facilitate the rational design of novel agonists and antagonists of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139, but also may guide the design of transgenic animal models to study the physiological function of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139.</jats:p> |
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author | Wang, Lien, Lee, Grace, Shih, Amy, Kuei, Chester, Nepomuceno, Diane, Wennerholm, Michelle, Fan, Frances, Wu, Jiejun, Bonaventure, Pascal, Lovenberg, Timothy W., Liu, Changlu |
author_facet | Wang, Lien, Lee, Grace, Shih, Amy, Kuei, Chester, Nepomuceno, Diane, Wennerholm, Michelle, Fan, Frances, Wu, Jiejun, Bonaventure, Pascal, Lovenberg, Timothy W., Liu, Changlu, Wang, Lien, Lee, Grace, Shih, Amy, Kuei, Chester, Nepomuceno, Diane, Wennerholm, Michelle, Fan, Frances, Wu, Jiejun, Bonaventure, Pascal, Lovenberg, Timothy W., Liu, Changlu |
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description | <jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">GPR</jats:styled-content>139 is a Gq‐coupled receptor activated by the essential amino acids L‐tryptophan (L‐Trp) and L‐phenylalanine (L‐Phe). We carried out mutagenesis studies of the human <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 receptor to identify the critical structural motifs required for <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 activation. We applied site‐directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 clones with gain‐of‐function, reduction‐of‐function or loss‐of‐function mutations. The agonist pharmacology of these mutant receptors was characterized and compared to wild‐type receptor using calcium mobilization, radioligand binding, and protein expression assays. The structure‐activity data were incorporated into a homology model which highlights that many of the gain‐of‐function mutations are either in or immediately adjacent to the purported orthosteric ligand binding site, whereas the loss‐of‐function mutations were largely in the intracellular G‐protein binding area or were disrupters of the helix integrity. There were also some reduction‐of‐function mutations in the orthosteric ligand binding site. These findings may not only facilitate the rational design of novel agonists and antagonists of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139, but also may guide the design of transgenic animal models to study the physiological function of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139.</jats:p> |
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spelling | Wang, Lien Lee, Grace Shih, Amy Kuei, Chester Nepomuceno, Diane Wennerholm, Michelle Fan, Frances Wu, Jiejun Bonaventure, Pascal Lovenberg, Timothy W. Liu, Changlu 2052-1707 2052-1707 Wiley General Pharmacology, Toxicology and Pharmaceutics Neurology http://dx.doi.org/10.1002/prp2.466 <jats:title>Abstract</jats:title><jats:p><jats:styled-content style="fixed-case">GPR</jats:styled-content>139 is a Gq‐coupled receptor activated by the essential amino acids L‐tryptophan (L‐Trp) and L‐phenylalanine (L‐Phe). We carried out mutagenesis studies of the human <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 receptor to identify the critical structural motifs required for <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 activation. We applied site‐directed and high throughput random mutagenesis approaches using a double addition normalization strategy to identify novel <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 sequences coding receptors that have altered sensitivity to endogenous ligands. This approach resulted in <jats:styled-content style="fixed-case">GPR</jats:styled-content>139 clones with gain‐of‐function, reduction‐of‐function or loss‐of‐function mutations. The agonist pharmacology of these mutant receptors was characterized and compared to wild‐type receptor using calcium mobilization, radioligand binding, and protein expression assays. The structure‐activity data were incorporated into a homology model which highlights that many of the gain‐of‐function mutations are either in or immediately adjacent to the purported orthosteric ligand binding site, whereas the loss‐of‐function mutations were largely in the intracellular G‐protein binding area or were disrupters of the helix integrity. There were also some reduction‐of‐function mutations in the orthosteric ligand binding site. These findings may not only facilitate the rational design of novel agonists and antagonists of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139, but also may guide the design of transgenic animal models to study the physiological function of <jats:styled-content style="fixed-case">GPR</jats:styled-content>139.</jats:p> Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors Pharmacology Research & Perspectives |
spellingShingle | Wang, Lien, Lee, Grace, Shih, Amy, Kuei, Chester, Nepomuceno, Diane, Wennerholm, Michelle, Fan, Frances, Wu, Jiejun, Bonaventure, Pascal, Lovenberg, Timothy W., Liu, Changlu, Pharmacology Research & Perspectives, Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors, General Pharmacology, Toxicology and Pharmaceutics, Neurology |
title | Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_full | Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_fullStr | Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_full_unstemmed | Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_short | Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
title_sort | mutagenesis of gpr139 reveals ways to create gain or loss of function receptors |
title_unstemmed | Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors |
topic | General Pharmacology, Toxicology and Pharmaceutics, Neurology |
url | http://dx.doi.org/10.1002/prp2.466 |