Comparing the Dynamic Differences between X-ray and Cryo-EM Structures of Cannabinoid Receptor 1 using Molecular Dynamics Simulations

Isu, Ugochi; Kumar, Vivek Govind; Polasa, Adithya; Moradi, Mahmoud

doi:10.1016/j.bpj.2020.11.424

Cited by 2 publications

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“…This is disrupted in the active state, enabling TM movements necessary for activation. 52,53 Therefore, these electrostatic interactions could constitute an integral regulatory mechanism controlling state-dependent CB1 dynamics. Our study sheds light on the dynamic context of the suggested rotating network of extracellular electrostatic interactions influencing CB1 function.…”

Section: Introductionmentioning

confidence: 99%

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

Isu,

Polasa,

Moradi

2024

Preprint

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The cannabinoid receptor CB1 is a G protein-coupled receptor that regulates critical physiological processes including pain, appetite, and cognition. Understanding the conformational dynamics of CB1 associated with transitions between inactive and active signaling states is imperative for developing targeted modulators. Using microsecond-level all-atom molecular dynamics simulations, we identified marked differences in the conformational ensembles of inactive and active CB1 states in apo conditions. The inactive state exhibited substantially increased structural heterogeneity and plasticity compared to the more rigidified active state in the absence of stabilizing ligands. Transmembrane helices TM3 and TM7 were identified as distinguishing factors modulating the state-dependent dynamics. TM7 displayed amplified fluctuations selectively in the inactive state simulations attributed to disruption of conserved electrostatic contacts anchoring it to surrounding helices in the active state. Additionally, we identified significant reorganization of key salt bridge and hydrogen bond networks known to control CB1 activation between states. For instance, a conserved D213-Y224 hydrogen bond and D184-K192 salt bridge interactions showed marked rearrangements between the states. Collectively, these findings reveal the specialized role of TM7 in directing state-dependent CB1 dynamics through electrostatic switch mechanisms. By elucidating the intrinsic enhanced flexibility of inactive CB1, this study provides valuable insights into the conformational landscape enabling functional transitions. Our perspective advances understanding of CB1 activation mechanisms and offers opportunities for structure-based drug discovery targeting the state-specific conformational dynamics of this receptor.

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Section: Introductionmentioning

confidence: 99%

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

Isu,

Polasa,

Moradi

2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

Isu,

Polasa,

Moradi

2024

J. Phys. Chem. B

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Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor that regulates critical physiological processes including pain, appetite, and cognition. Understanding the conformational dynamics of CB1 associated with transitions between inactive and active signaling states is imperative for developing targeted modulators. Using microsecond-level all-atom molecular dynamics simulations, we identified marked differences in the conformational ensembles of inactive and active CB1 in apo. The inactive state exhibited substantially increased structural heterogeneity and plasticity compared to the more rigidified active state in the absence of stabilizing ligands. Transmembrane helices TM3 and TM7 were identified as distinguishing factors modulating the state-dependent dynamics. TM7 displayed amplified fluctuations selectively in the inactive state simulations attributed to disruption of conserved electrostatic contacts anchoring it to surrounding helices in the active state. Additionally, we identified significant reorganizations in key salt bridge and hydrogen bond networks contributing to the CB1 activation/inactivation. For instance, D213-Y224 hydrogen bond and D184-K192 salt bridge showed marked rearrangements between the states. Collectively, these findings reveal the specialized role of TM7 in directing statedependent CB1 dynamics through electrostatic switch mechanisms. By elucidating the intrinsic enhanced flexibility of inactive CB1, this study provides valuable insights into the conformational landscape enabling functional transitions. Our perspective advances understanding of CB1 activation mechanisms and offers opportunities for structure-based drug discovery targeting the state-specific conformational dynamics of this receptor.

show abstract

Comparing the Dynamic Differences between X-ray and Cryo-EM Structures of Cannabinoid Receptor 1 using Molecular Dynamics Simulations

Cited by 2 publications

References 0 publications

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1

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