Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Draper-Joyce, Christopher J; Bhola, Rebecca F.; Wang, Jinan; Bhattarai, Apurba; Nguyen, Thi Ngoc Anh; Cowie-Kent, India; O’Sullivan, Kelly; Chia, Ling Yeong; Venugopal, Hariprasad; Valant, Céline; Thal, David M.; Wootten, Denise; Panel, Nicolas; Carlsson, Jens; Christie, MacDonald J.; White, Paul; Scammells, Peter J.; May, Lauren T.; Sexton, Patrick M.; Danev, Radostin; Miao, Yinglong; Glukhova, Alisa; Imlach, Wendy L.; Christopoulos, Arthur

doi:10.1038/s41586-021-03897-2

Cited by 107 publications

(173 citation statements)

References 71 publications

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“…In line with class A of GPCR, the Gs protein has a stabilizing effect on the ABD and IBD of GCGR to keep the fully active state of the receptor. Previous single-molecule fluorescence spectroscopy (FRET) provided a detailed explanation for the increased agonist efficacy observed with a positive agonist modulator (PAM) [102] . We here revealed that NAM can allosterically influence the glucagon binding affinity.…”

Section: Discussionmentioning

confidence: 99%

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Wang

Liang

et al. 2022

Computational and Structural Biotechnology Journal

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Section: Discussionmentioning

confidence: 99%

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Wang

Liang

et al. 2022

Computational and Structural Biotechnology Journal

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“…Then 24 ns GaMD equilibration after applying the boost potential was performed. Previous studies showed that hundreds-of-nanosecond GaMD simulations with multiple replicas could provide good sampling of native biomolecular complexes( Miao and McCammon, 2016a , Miao and McCammon, 2016b ; Bhattarai et al., 2020 ; Draper-Joyce et al., 2021 ; Wang and Miao, 2019 ) and microsecond GaMD simulations were able to capture ligand binding from solvent to target proteins( Miao and McCammon, 2016a , Miao and McCammon, 2016b ; Pawnikar and Miao, 2020 ; Miao et al., 2018 ). Therefore, 3 independent 500 ns GaMD simulations with randomized initial atomic velocities were performed on the MSI1-Numb bound system ( Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of RNA recognition by a Musashi RNA-binding protein

Wang

Lan

et al. 2022

Current Research in Structural Biology

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The Musashi RNA-binding proteins (RBPs) regulate translation of target mRNAs and maintenance of cell stemness and tumorigenesis. Musashi-1 (MSI1), long considered as an intestinal and neural stem cell marker, has been more recently found to be over expressed in many cancers. It has served as an important drug target for treating acute myeloid leukemia and solid tumors such as ovarian, colorectal and bladder cancer. One of the reported binding targets of MSI1 is Numb, a negative regulator of the Notch signaling. However, the dynamic mechanism of Numb RNA binding to MSI1 remains unknown, largely hindering effective drug design targeting this critical interaction. Here, we have performed extensive all-atom microsecond-timescale simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which successfully captured multiple times of spontaneous and highly accurate binding of the Numb RNA from bulk solvent to the MSI1 protein target site. GaMD simulations revealed that Numb RNA binding to MSI1 involved largely induced fit in both the RNA and protein. The simulations also identified important low-energy intermediate conformational states during RNA binding, in which Numb interacted mainly with the β2-β3 loop and C terminus of MSI1. The mechanistic understanding of RNA binding obtained from our GaMD simulations is expected to facilitate rational structure-based drug design targeting MSI1 and other RBPs.

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“…The AR-PAMs that have been developed so far display only moderate potency or selectivity, and their usefulness is still unclear ( Fredholm et al, 2011 ; Göblyös and IJzerman, 2011 ; Jacobson et al, 2011 ; Müller et al, 2012 ; Nguyen et al, 2016 ; Barresi et al, 2021 ). Interestingly, in a recent cryo-EM structure of the A 1 AR, a PAM (MIPS521) was found to be localized in an extrahelical domain ( Draper-Joyce et al, 2021 ). MIPS521’s analgesic properties were evaluated in the same paper, reminiscent of earlier attempts to profile another PAM as a potential painkiller ( Kiesman et al, 2009 ).…”

Section: Receptor Ligands (For Structures See Figs 1 ...mentioning

confidence: 99%

“…Thirdly, complexation of the A 2A AR with antibodies raised against epitopes of the receptor provided sufficient stability to render X-ray crystallography feasible ( Hino et al, 2012 ). In recent years, cryogenic electron microscopy (EM), particularly single-particle cryo-EM ( Cheng, 2018 ; Ceska et al, 2019 ), has been employed to study membrane protein structures as well, including agonist-bound structures of the A 1 AR ( Draper-Joyce et al, 2018 ; 2021 ) and A 2A AR (Garcia-Nafria et al, 2018) in complex with G protein variants.…”

Section: Receptor Structuresmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

et al. 2022

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Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. Significance Statement Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists (“biased” or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A 2A - and A 2B AR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A 2A AR antagonist (istradefylline) has been approved as an anti-Parkinson agent.

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Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Cited by 107 publications

References 71 publications

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Mechanism of RNA recognition by a Musashi RNA-binding protein

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

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