Molecular determinants of GPCR pharmacogenetics: Deconstructing the population variants in β2-adrenergic receptor

Joshi, M. P.; Nikte, Siddhanta V.; Sengupta, Durba

doi:10.1016/bs.apcsb.2021.08.002

Cited by 3 publications

References 84 publications

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Unraveling the Structural Basis of Biased Agonism in the β₂‐Adrenergic Receptor Through Molecular Dynamics Simulations

Plazinski,

Archala,

Jozwiak

et al. 2024

Proteins

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Biased agonism in G protein‐coupled receptors is a phenomenon resulting in the selective activation of distinct intracellular signaling pathways by different agonists, which may exhibit bias toward either Gs, Gi, or arrestin‐mediated pathways. This study investigates the structural basis of ligand‐induced biased agonism within the context of the β2‐adrenergic receptor (β2‐AR). Atomistic molecular dynamics simulations were conducted for β2‐AR complexes with two stereoisomers of methoxynaphtyl fenoterol (MNFen), that is, compounds eliciting qualitatively different cellular responses. The simulations reveal distinct interaction patterns within the binding cavity, dependent on the stereoisomer. These changes propagate to the intracellular parts of the receptor, triggering various structural responses: the dynamic structure of the intracellular regions of the (R,R)‐MNFen complex more closely resembles the “Gs‐compatible” and “β‐arrestin‐compatible” conformation of β2‐AR, while both stereoisomers maintain structural responses equidistant from the inactive conformation. These findings are confirmed by independent coarse‐grained simulations. In the context of deciphered molecular mechanisms, Trp313 plays a pivotal role, altering its orientation upon interactions with (R,R)‐MNFen, along with the Lys305‐Asp192 ionic bridge. This effect, accompanied by ligand interactions with residues on TM2, increases the strength of interactions within the extracellular region and the binding cavity, resulting in a slightly more open conformation and a minor (by ca. 0.2 nm) increase in the distance between the TM5–TM7, TM1–TM6, TM6–TM7, and TM1–TM5 pairs. On the other hand, an even slighter decrease in the distance between the TM1–TM4 and TM2–TM4 pairs is observed.

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Unraveling the Structural Basis of Biased Agonism in the β₂‐Adrenergic Receptor Through Molecular Dynamics Simulations

Plazinski,

Archala,

Jozwiak

et al. 2024

Proteins

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Diversity and specificity in location-based signaling outputs of neuronal GPCRs

Kumar

Puthenveedu

2022

Current Opinion in Neurobiology

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A Two-Step Enzymatic Cascade for Synthesis of Diverse Ephedra-Type Alkaloids

Wu,

Luo,

Wang

et al. 2024

Preprint

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Molecular determinants of GPCR pharmacogenetics: Deconstructing the population variants in β2-adrenergic receptor

Cited by 3 publications

References 84 publications

Unraveling the Structural Basis of Biased Agonism in the β₂‐Adrenergic Receptor Through Molecular Dynamics Simulations

Unraveling the Structural Basis of Biased Agonism in the β₂‐Adrenergic Receptor Through Molecular Dynamics Simulations

Diversity and specificity in location-based signaling outputs of neuronal GPCRs

A Two-Step Enzymatic Cascade for Synthesis of Diverse Ephedra-Type Alkaloids

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Molecular determinants of GPCR pharmacogenetics: Deconstructing the population variants in β2-adrenergic receptor

Cited by 3 publications

References 84 publications

Unraveling the Structural Basis of Biased Agonism in the β2‐Adrenergic Receptor Through Molecular Dynamics Simulations

Unraveling the Structural Basis of Biased Agonism in the β2‐Adrenergic Receptor Through Molecular Dynamics Simulations

Diversity and specificity in location-based signaling outputs of neuronal GPCRs

A Two-Step Enzymatic Cascade for Synthesis of Diverse Ephedra-Type Alkaloids

Contact Info

Product

Resources

About

Unraveling the Structural Basis of Biased Agonism in the β₂‐Adrenergic Receptor Through Molecular Dynamics Simulations

Unraveling the Structural Basis of Biased Agonism in the β₂‐Adrenergic Receptor Through Molecular Dynamics Simulations