Mechanism of β
            <sub>2</sub>
            AR regulation by an intracellular positive allosteric modulator

Liu, Xiangyu; Masoudi, Ali; Kahsai, Alem W.; Huang, Lin; Pani, Biswaranjan; Staus, Dean P.; Shim, Paul J.; Hirata, Kunio; Simhal, Rishabh K.; Schwalb, Allison M.; Rambarat, Paula; Ahn, Seungkirl; Lefkowitz, Robert J.; Kobilka, Brian K.

doi:10.1126/science.aaw8981

Cited by 99 publications

(123 citation statements)

References 47 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…3 D ). This interaction is essential for G s activation ( 4 , 23 , 24 ). The conformational changes detected in the NMR spectra of K147 4.39 and K140 34.52 may represent the chemical environment change during the transition of ICL2 from a loop to a helix ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of β ₂ AR-G _s and β ₂ AR-G _i complex formation by NMR spectroscopy

Batebi³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor (GPCR) that preferentially couples to the stimulatory G protein Gs and stimulates cAMP formation. Functional studies have shown that the β2AR also couples to inhibitory G protein Gi, activation of which inhibits cAMP formation [R. P. Xiao, Sci. STKE 2001, re15 (2001)]. A crystal structure of the β2AR-Gs complex revealed the interaction interface of β2AR-Gs and structural changes upon complex formation [S. G. Rasmussen et al., Nature 477, 549–555 (2011)], yet, the dynamic process of the β2AR signaling through Gs and its preferential coupling to Gs over Gi is still not fully understood. Here, we utilize solution nuclear magnetic resonance (NMR) spectroscopy and supporting molecular dynamics (MD) simulations to monitor the conformational changes in the G protein coupling interface of the β2AR in response to the full agonist BI-167107 and Gs and Gi1. These results show that BI-167107 stabilizes conformational changes in four transmembrane segments (TM4, TM5, TM6, and TM7) prior to coupling to a G protein, and that the agonist-bound receptor conformation is different from the G protein coupled state. While most of the conformational changes observed in the β2AR are qualitatively the same for Gs and Gi1, we detected distinct differences between the β2AR-Gs and the β2AR-Gi1 complex in intracellular loop 2 (ICL2). Interactions with ICL2 are essential for activation of Gs. These differences between the β2AR-Gs and β2AR-Gi1 complexes in ICL2 may be key determinants for G protein coupling selectivity.

show abstract

Section: Resultsmentioning

confidence: 99%

Analysis of β ₂ AR-G _s and β ₂ AR-G _i complex formation by NMR spectroscopy

Batebi³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…10 Binding sites of allosteric modulators in GPCRs reported after October 2018, in comparison with related ligands. a NAM ORG27569 in CB1 (PDB code: 6KQI 166 ) in comparison with cholesterol (PDB code: 5XRA 179 ); b NAM AS408 (PDB code: 6OBA 180 ) and PAM Cmpd-6FA (PDB code: 6N48 181 ) in β 2 AR, in comparison with NDT9513727 in C5AR1 (PDB code: 6C1Q 182 ) and PAM AP8 (PDB code: 5TZY 183 ); c NAM maraviroc in CCR5 (PDB code: 4MBS 187 ) in comparison with chemokine analog antagonist [5P7]CCL5 (PDB code: 5UIW 188 ) and HIV envelope glycoprotein gp120 (PDB code: 6MEO 189 ); d PAM TT-OAD2 in GLP-1R (PDB code: 6ORV 190 ) in comparison with GLP-1 (PDB code: 5VAI 191 ) …”

Section: Gpcr Pharmacologymentioning

confidence: 99%

G protein-coupled receptors: structure- and function-based drug discovery

Yang

Zhou

Labroska

et al. 2021

Sig Transduct Target Ther

372

280

View full text Add to dashboard Cite

As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure–function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.

show abstract

“…There are three published reports of allosteric modulation at α 1 -ARs, and all are described as negative allosteric modulators with no known clinically-useful application as of yet ( Leppik et al., 2000 ; Sharpe et al., 2003 ; Campbell et al., 2017 ). Positive allosteric modulators have also been developed for the β 2 -AR ( Ahn et al., 2018 ; Liu et al., 2019 ). While these modulators are selective for the β 2 -AR and display cooperative signals with agonists, they are not ligand-selective nor signaling-biased.…”

Section: Drug Development and Allosteric Modulatorsmentioning

confidence: 99%

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

Perez

2020

Front. Pharmacol.

View full text Add to dashboard Cite

a 1-adrenergic receptors are G-Protein Coupled Receptors that are involved in neurotransmission and regulate the sympathetic nervous system through binding and activating the neurotransmitter, norepinephrine, and the neurohormone, epinephrine. There are three a 1-adrenergic receptor subtypes (a 1A , a 1B , a 1D) that are known to play various roles in neurotransmission and cognition. They are related to two other adrenergic receptor families that also bind norepinephrine and epinephrine, the band a 2-, each with three subtypes (b 1 , b 2 , b 3 , a 2A , a 2B , a 2C). Previous studies assessing the roles of a 1-adrenergic receptors in neurotransmission and cognition have been inconsistent. This was due to the use of poorly-selective ligands and many of these studies were published before the characterization of the cloned receptor subtypes and the subsequent development of animal models. With the availability of more-selective ligands and the development of animal models, a clearer picture of their role in cognition and neurotransmission can be assessed. In this review, we highlight the significant role that the a 1-adrenergic receptor plays in regulating synaptic efficacy, both short and long-term synaptic plasticity, and its regulation of different types of memory. We will also present evidence that the a 1-adrenergic receptors, and particularly the a 1A-adrenergic receptor subtype, are a potentially good target to treat a wide variety of neurological conditions with diminished cognition.

show abstract

Mechanism of β ₂ AR regulation by an intracellular positive allosteric modulator

Cited by 99 publications

References 47 publications

Analysis of β ₂ AR-G _s and β ₂ AR-G _i complex formation by NMR spectroscopy

Analysis of β ₂ AR-G _s and β ₂ AR-G _i complex formation by NMR spectroscopy

G protein-coupled receptors: structure- and function-based drug discovery

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

Contact Info

Product

Resources

About

Mechanism of β 2 AR regulation by an intracellular positive allosteric modulator

Cited by 99 publications

References 47 publications

Analysis of β 2 AR-G s and β 2 AR-G i complex formation by NMR spectroscopy

Analysis of β 2 AR-G s and β 2 AR-G i complex formation by NMR spectroscopy

G protein-coupled receptors: structure- and function-based drug discovery

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

Contact Info

Product

Resources

About

Mechanism of β ₂ AR regulation by an intracellular positive allosteric modulator

Analysis of β ₂ AR-G _s and β ₂ AR-G _i complex formation by NMR spectroscopy

Analysis of β ₂ AR-G _s and β ₂ AR-G _i complex formation by NMR spectroscopy