ArticleComputational and structural biotechnology journal2022
Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor.
Article in Computational and structural biotechnology journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 57 citations in OpenAlex.
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- Exploring the constitutive activation mechanism of the class A orphan GPR20.Acta pharmacologica Sinica · 2025Article
- Computational Insights into Acrylamide Fragment Inhibition of SARS-CoV-2 Main Protease.Current issues in molecular biology · 2024Article
- Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5.Nature communications · 2024Article
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- Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters.Mini reviews in medicinal chemistry · 2024Review
- Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations.Journal of enzyme inhibition and medicinal chemistry · 2023Article
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- Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators.Communications chemistry · 2023Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
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- Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations.Molecules (Basel, Switzerland) · 2023Article
- Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase-Calmodulin Interaction.Biomolecules · 2022Article
- Mechanistic Understanding of the Palmitoylation of GPharmaceutics · 2022Article
- Deciphering Conformational Changes of the GDP-Bound NRAS Induced by Mutations G13D, Q61R, and C118S through Gaussian Accelerated Molecular Dynamic Simulations.Molecules (Basel, Switzerland) · 2022Article
- Understanding gilteritinib resistance to FLT3-F691L mutation through an integrated computational strategy.Journal of molecular modeling · 2022Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Class B G protein-coupled receptors (GPCRs) are important targets in the treatment of metabolic syndrome and diabetes. Although multiple structures of class B GPCRs-G protein complexes have been elucidated, the detailed activation mechanism of the receptors remains unclear. Here, we combine Gaussian accelerated molecular dynamics simulations and Markov state models (MSM) to investigate the activation mechanism of a canonical class B GPCR, human glucagon receptor-GCGR, including the negative allosteric modulator-bound inactive state, the agonist glucagon-bound active state, and both glucagon- and Gs-bound fully active state. The free-energy landscapes of GCGR show the conformational ensemble consisting of three activation-associated states: inactive, active, and fully active. The structural analysis indicates the high dynamics of GCGR upon glucagon binding with both active and inactive conformations in the ensemble. Significantly, the H8 and TM6 exhibits distinct features from the inactive to the active states. The additional simulations demonstrate the role of H8 in the recruitment of Gs. Gs binding presents a crucial function of stabilizing the glucagon binding site and MSM highlights the absolute requirement of Gs to help the GCGR reach the fully active state. Together, our results reveal the detailed activation mechanism of GCGR from the view of conformational dynamics.
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