Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics
Abstract G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1 and β2 adrenergic rece...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-37808-y |
| _version_ | 1797817884344320000 |
|---|---|
| author | Xinyu Xu Jeremy Shonberg Jonas Kaindl Mary J. Clark Anne Stößel Luis Maul Daniel Mayer Harald Hübner Kunio Hirata A. J. Venkatakrishnan Ron O. Dror Brian K. Kobilka Roger K. Sunahara Xiangyu Liu Peter Gmeiner |
| author_facet | Xinyu Xu Jeremy Shonberg Jonas Kaindl Mary J. Clark Anne Stößel Luis Maul Daniel Mayer Harald Hübner Kunio Hirata A. J. Venkatakrishnan Ron O. Dror Brian K. Kobilka Roger K. Sunahara Xiangyu Liu Peter Gmeiner |
| author_sort | Xinyu Xu |
| collection | DOAJ |
| description | Abstract G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1 and β2 adrenergic receptors (β1AR and β2AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β2AR over the β1AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β2AR, as well as a less stable binding pocket for constrained epinephrine in the β1AR. The differences in the amino acid sequence of the extracellular vestibule of the β1AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β2AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs. |
| first_indexed | 2024-03-13T09:00:04Z |
| format | Article |
| id | doaj.art-06de6af761474c2b9a90d90838043ba7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T09:00:04Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-06de6af761474c2b9a90d90838043ba72023-05-28T11:20:55ZengNature PortfolioNature Communications2041-17232023-04-0114111310.1038/s41467-023-37808-yConstrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamicsXinyu Xu0Jeremy Shonberg1Jonas Kaindl2Mary J. Clark3Anne Stößel4Luis Maul5Daniel Mayer6Harald Hübner7Kunio Hirata8A. J. Venkatakrishnan9Ron O. Dror10Brian K. Kobilka11Roger K. Sunahara12Xiangyu Liu13Peter Gmeiner14State Key laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-NurnbergDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-NurnbergDepartment of Pharmacology, University of California San Diego School of MedicineDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-NurnbergDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-NurnbergDepartment of Pharmacology, University of California San Diego School of MedicineDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-NurnbergAdvanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 CenterDepartment of Computer Science, Stanford UniversityDepartment of Computer Science, Stanford UniversityDepartment of Molecular and Cellular Physiology, Stanford University School of MedicineDepartment of Pharmacology, University of California San Diego School of MedicineState Key laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-NurnbergAbstract G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1 and β2 adrenergic receptors (β1AR and β2AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β2AR over the β1AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β2AR, as well as a less stable binding pocket for constrained epinephrine in the β1AR. The differences in the amino acid sequence of the extracellular vestibule of the β1AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β2AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.https://doi.org/10.1038/s41467-023-37808-y |
| spellingShingle | Xinyu Xu Jeremy Shonberg Jonas Kaindl Mary J. Clark Anne Stößel Luis Maul Daniel Mayer Harald Hübner Kunio Hirata A. J. Venkatakrishnan Ron O. Dror Brian K. Kobilka Roger K. Sunahara Xiangyu Liu Peter Gmeiner Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics Nature Communications |
| title | Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics |
| title_full | Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics |
| title_fullStr | Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics |
| title_full_unstemmed | Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics |
| title_short | Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics |
| title_sort | constrained catecholamines gain β2ar selectivity through allosteric effects on pocket dynamics |
| url | https://doi.org/10.1038/s41467-023-37808-y |
| work_keys_str_mv | AT xinyuxu constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT jeremyshonberg constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT jonaskaindl constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT maryjclark constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT annestoßel constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT luismaul constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT danielmayer constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT haraldhubner constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT kuniohirata constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT ajvenkatakrishnan constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT ronodror constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT briankkobilka constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT rogerksunahara constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT xiangyuliu constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics AT petergmeiner constrainedcatecholaminesgainb2arselectivitythroughallostericeffectsonpocketdynamics |