Molecular Mechanism of Action of Pharmacoperone Rescue of Misrouted GPCR Mutants: The GnRH Receptor
The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mu...
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Published in | Molecular endocrinology (Baltimore, Md.) Vol. 23; no. 2; pp. 157 - 168 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Endocrine Society
01.02.2009
Oxford University Press The Endocrine Society |
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Abstract | The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy. Our results show that two different chemical classes of pharmacoperones act to stabilize hGnRHR mutants by bridging residues D98 and K121. This ligand-mediated bridge serves as a surrogate for a naturally occurring and highly conserved salt bridge (E90–K121) that stabilizes the relation between transmembranes 2 and 3, which is required for passage of the receptor through the cellular quality control system and to the plasma membrane. Our model was used to reveal important pharmacophoric features, and then identify a novel chemical ligand, which was able to rescue a D98 mutant of the hGnRHR that could not be rescued as effectively by previously known pharmacoperones.
Computational modeling, site-directed mutagenesis, ligand binding, effector activation and confocal microscopy are used to show the molecular mechanism of pharmacoperone action on a GPCR, the hGnRHR. |
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AbstractList | The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy. Our results show that two different chemical classes of pharmacoperones act to stabilize hGnRHR mutants by bridging residues D
98
and K
121
. This ligand-mediated bridge serves as a surrogate for a naturally occurring and highly conserved salt bridge (E
90
–K
121
) that stabilizes the relation between transmembranes 2 and 3, which is required for passage of the receptor through the cellular quality control system and to the plasma membrane. Our model was used to reveal important pharmacophoric features, and then identify a novel chemical ligand, which was able to rescue a D
98
mutant of the hGnRHR that could not be rescued as effectively by previously known pharmacoperones.
Computational modeling, site-directed mutagenesis, ligand binding, effector activation and confocal microscopy are used to show the molecular mechanism of pharmacoperone action on a GPCR, the hGnRHR. The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy. Our results show that two different chemical classes of pharmacoperones act to stabilize hGnRHR mutants by bridging residues D(98) and K(121). This ligand-mediated bridge serves as a surrogate for a naturally occurring and highly conserved salt bridge (E(90)-K(121)) that stabilizes the relation between transmembranes 2 and 3, which is required for passage of the receptor through the cellular quality control system and to the plasma membrane. Our model was used to reveal important pharmacophoric features, and then identify a novel chemical ligand, which was able to rescue a D(98) mutant of the hGnRHR that could not be rescued as effectively by previously known pharmacoperones. Abstract The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy. Our results show that two different chemical classes of pharmacoperones act to stabilize hGnRHR mutants by bridging residues D98 and K121. This ligand-mediated bridge serves as a surrogate for a naturally occurring and highly conserved salt bridge (E90–K121) that stabilizes the relation between transmembranes 2 and 3, which is required for passage of the receptor through the cellular quality control system and to the plasma membrane. Our model was used to reveal important pharmacophoric features, and then identify a novel chemical ligand, which was able to rescue a D98 mutant of the hGnRHR that could not be rescued as effectively by previously known pharmacoperones. The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy. Our results show that two different chemical classes of pharmacoperones act to stabilize hGnRHR mutants by bridging residues D98 and K121. This ligand-mediated bridge serves as a surrogate for a naturally occurring and highly conserved salt bridge (E90–K121) that stabilizes the relation between transmembranes 2 and 3, which is required for passage of the receptor through the cellular quality control system and to the plasma membrane. Our model was used to reveal important pharmacophoric features, and then identify a novel chemical ligand, which was able to rescue a D98 mutant of the hGnRHR that could not be rescued as effectively by previously known pharmacoperones. Computational modeling, site-directed mutagenesis, ligand binding, effector activation and confocal microscopy are used to show the molecular mechanism of pharmacoperone action on a GPCR, the hGnRHR. |
Author | Patny, Akshay Rush, Thomas S Altman, Michael D Goulet, Mark T Janovick, Jo Ann Mosley, Ralph Conn, P. Michael Cornea, Anda |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/19095769$$D View this record in MEDLINE/PubMed |
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Copyright | Copyright © 2009 by The Endocrine Society 2009 Copyright © 2009 by The Endocrine Society 2009 |
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Notes | Address all correspondence and requests for reprints to: P. Michael Conn, Oregon National Primate Research Center/Oregon Health Sciences University, 505 North West 185th Avenue, Beaverton, Oregon 97006. E-mail: connm@ohsu.edu. |
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Snippet | The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue... Abstract The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs... |
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SubjectTerms | Animals Cattle Cell Membrane - metabolism Computer Simulation Humans Ligands Models, Molecular Molecular Chaperones - metabolism Molecular Structure Mutagenesis, Site-Directed Mutation Protein Binding Protein Conformation Protein Transport - physiology Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, LHRH - genetics Receptors, LHRH - metabolism |
Title | Molecular Mechanism of Action of Pharmacoperone Rescue of Misrouted GPCR Mutants: The GnRH Receptor |
URI | http://dx.doi.org/10.1210/me.2008-0384 https://www.ncbi.nlm.nih.gov/pubmed/19095769 https://pubmed.ncbi.nlm.nih.gov/PMC2646616 |
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