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An allosteric modulator binds to a conformational hub in the ?₂ adrenergic receptor.

ABSTRACT: Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the ?₂-adrenergic receptor (?₂AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E122^3.41 and the backbone carbonyls of V206^5.45 and S207^5.46. The AS408 binding site is adjacent to a previously identified molecular switch for ?₂AR activation formed by I^3.40, P^5.50 and F^6.44. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.

SUBMITTER: Liu X

PROVIDER: S-EPMC7816728 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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An allosteric modulator binds to a conformational hub in the β2 adrenergic receptor.

Liu Xiangyu X Kaindl Jonas J Korczynska Magdalena M Stößel Anne A Dengler Daniela D Stanek Markus M Hübner Harald H Clark Mary J MJ Mahoney Jake J Matt Rachel Ann RA Xu Xinyu X Hirata Kunio K Shoichet Brian K BK Sunahara Roger K RK Kobilka Brian K BK Gmeiner Peter P

Nature chemical biology 20200601 7

Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the β2-adrenergic receptor (β2AR), AS408, that binds to the membrane-facing surface of transmembrane segme ...[more]

PMID: 32483378

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Project description:Rationale: Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "?5-PAM"), a positive allosteric modulator selective for ?5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with ?5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic ?5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic ?5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to ?5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with ?5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of ?5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

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An allosteric modulator binds to a conformational hub in the ?₂ adrenergic receptor.

Publications

An allosteric modulator binds to a conformational hub in the β<sub>2</sub> adrenergic receptor.

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Dataset Information

An allosteric modulator binds to a conformational hub in the ?2 adrenergic receptor.

Publications

An allosteric modulator binds to a conformational hub in the β<sub>2</sub> adrenergic receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

An allosteric modulator binds to a conformational hub in the ?₂ adrenergic receptor.