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

Wang, Ying; Li, Mingyu; Liang, Wenqi; Shi, Xinchao; Fan, Jigang; Kong, Ren; Liu, Yaqin; Zhang, Jian; Chen, Ting; Lu, Shaoyong

doi:10.1016/j.csbj.2022.01.015

Cited by 45 publications

(24 citation statements)

References 103 publications

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“…Molecular dynamics (MD) simulations that explore protein and nucleic acid conformational dynamics at the atomic level are critical for understanding of target repression and TDMD process [37] , [38] , [39] , [40] , [41] , [42] , [43] . In the recent work, we have used MD simulations to directly uncover biomolecular mechanisms and protein–ligand/protein or protein–DNA/RNA recognitions [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] . Previous investigations on AGO utilizing large-scale MD simulations have successfully illuminated detailed mechanisms behind AGO-RNA interaction [58] , [59] , [60] and have been testified by experiments [61] .…”

Section: Introductionmentioning

confidence: 99%

Elucidation of the conformational dynamics and assembly of Argonaute–RNA complexes by distinct yet coordinated actions of the supplementary microRNA

Zhuang

Fan

et al. 2022

Computational and Structural Biotechnology Journal

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Section: Introductionmentioning

confidence: 99%

Elucidation of the conformational dynamics and assembly of Argonaute–RNA complexes by distinct yet coordinated actions of the supplementary microRNA

Zhuang

Fan

et al. 2022

Computational and Structural Biotechnology Journal

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“…Understanding these fundamental activation processes will not only increase our understanding of the physiological circumstances that govern GPR126-mediated functions, but it will also set the stage for allosteric pharmaceutical targeting of this ( Lu and Zhang, 2019 ) and potentially other aGPCRs. Allosteric modulation of a GPCR is of high pharmaceutical interest as it induces intermediate activation states, which potentially form the basis for activity-specific and biased modulation of signaling pathways ( Ni et al, 2020 ; Lu et al, 2021a ; Lu et al, 2021b ; Wang et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator

Mitgau¹,

Franke

Schinner

et al. 2022

Front. Cell Dev. Biol.

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The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner.

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“…Generalized correlation (GC ij ) analysis was performed to monitor the correlated motions of residues ( He et al, 2022 ; Wang et al, 2022 ; Zhuang et al, 2022 ). To describe that how much information of one atom was provided by another atom, Mutual Information (MI) was calculated using the Eq.…”

Section: Methodsmentioning

confidence: 99%

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

Liu

et al. 2022

Front. Mol. Biosci.

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As a member of the death-associated protein kinase family of serine/threonine kinases, the STK17B has been associated with diverse diseases such as hepatocellular carcinoma. However, the conformational dynamics of the phosphate-binding loop (P-loop) in the determination of inhibitor selectivity profile to the STK17B are less understood. Here, a multi-microsecond length molecular dynamics (MD) simulation of STK17B in the three different states (ligand-free, ADP-bound, and ligand-bound states) was carried out to uncover the conformational plasticity of the P-loop. Together with the analyses of principal component analysis, cross-correlation and generalized correlation motions, secondary structural analysis, and community network analysis, the conformational dynamics of the P-loop in the different states were revealed, in which the P-loop flipped into the ADP-binding site upon the inhibitor binding and interacted with the inhibitor and the C-lobe, strengthened the communication between the N- and C-lobes. These resulting interactions contributed to inhibitor selectivity profile to the STK17B. Our results may advance our understanding of kinase inhibitor selectivity and offer possible implications for the design of highly selective inhibitors for other protein kinases.

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

Abstract: Graphical abstract

Cited by 45 publications

References 103 publications

Elucidation of the conformational dynamics and assembly of Argonaute–RNA complexes by distinct yet coordinated actions of the supplementary microRNA

Elucidation of the conformational dynamics and assembly of Argonaute–RNA complexes by distinct yet coordinated actions of the supplementary microRNA

The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

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