Exploring the Activation Mechanism of a Metabotropic Glutamate Receptor Homodimer via Molecular Dynamics Simulation

Lei, Ting; Hu, Zhenxin; Ding, Ruolin; Chen, Jianfang; Li, Shiqi; Zhang, Fuhui; Pu, Xuemei; Zhao, Nanrong

doi:10.1021/acschemneuro.9b00425

Cited by 13 publications

(12 citation statements)

References 108 publications

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“…T is the temperature, while S is the total conformational entropy. Following some high-quality computational works, ,, the entropy contribution is not considered here, due to the very high computational cost and computing resource requirements. Furthermore, our main objective is to compare the relative binding affinities between the different agonists and β2AR, while the contribution of conformational entropy is similar for structurally similar small molecules .…”

Section: Methodsmentioning

confidence: 99%

“…MD simulations can provide a full picture of the structure changes over time at atomic resolution, , which has become a powerful tool to investigate protein structural and functional mechanisms, including GPCRs. − However, MD research on the biased activation of GPCRs is very limited despite a large number of GPCR works reported. In 2013, Tikhonova et al performed 370 ns accelerated MD simulations to investigate the changes of receptor conformations and water channels at β2AR during the transition from the active state to the inactive state upon binding biased ligands CPB and Sal, but the allosteric regulation of the biased ligands was not involved.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Mechanisms of Diverse Activation Stimulated by Different Biased Agonists for the β2-Adrenergic Receptor

Chen

Liu

Yuan

et al. 2021

J. Chem. Inf. Model.

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β2AR is an important drug target protein involving many diseases. Biased drugs induce specific signaling and provide additional clinical utility to optimize β2AR-based therapies. However, the biased signaling mechanism has not been elucidated. Motivated by the issue, we chose four agonists with divergent bias (balanced agonist, G-protein-biased agonist, and β-arrestin-biased agonists) and utilized Gaussian accelerated molecular dynamics simulation coupled with a dynamic network to probe the molecular mechanisms of distinct biased activation induced by the structural differences between the four agonists. Our simulations reveal that the G-protein-biased agonist induces an open conformation with the outward shifts of TM6 and TM7 for the intracellular domain, which will be beneficial to couple G protein. In contrast, the β-arrestin-biased agonists regulate an occluded conformation with a slightly outward movement of TM6 and an inward shift of TM7, which should favor β-arrestin signaling. The balanced agonist does not induce an observable outward shift for TM6 but, along with a slight tilt for TM7, leads to an inactive-like conformation. In addition, our results reveal the first time that ICL3 presents specific conformations with different agonists. The G-protein-biased agonist drives ICL3 to open so that the G protein-binding pocket can be available, while the β-arrestin-biased agonists induce ICL3 to form a closed conformation with a stable local α-helix. MM/PBSA analysis further reveals that the hydroxyl groups in the resorcinol of the G-protein-biased agonist form strong interactions with Y5.38 and S5.42, thus preventing tilting of the TM5 extracellular end. The catechol of the balanced agonist and the β-arrestin-biased ones induces the rearrangement of two hydrophobic residues F6.52 and W6.48. However, different from the balanced agonist, the ethyl substituent of β-arrestin-biased agonists forms additional hydrophobic interactions with W6.48 and F6.51 after the rearrangement, which should contribute to the β-arrestin bias. The shortest pathway analysis further reveals that the three residues Y7.43, N7.45, and N7.49 are crucial for allosterically regulating G-protein-biased signaling, while the two residues W6.48 and F6.44 make an important contribution to regulate β-arrestin-biased signaling. For the balanced agonist NE, the allosteric regulation pathway simultaneously involves the residue associated with G-protein-biased signaling like S5.46 and the residues related to β-arrestin-biased signaling like W6.48 and F6.44, thus producing unbiased signaling. The observations could advance our understanding of the biased activation mechanism on class A GPCRs and provide a useful guideline for the design of biased drugs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Diverse Activation Stimulated by Different Biased Agonists for the β2-Adrenergic Receptor

Chen

Liu

Yuan

et al. 2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The exact mechanisms of how the activation signal is transduced from the ligandbound VFT to the 7TM bundle are emerging, and it is thought that ligand binding induces inter-and intra-protomer conformational changes that result in 7TM activation (Fig. 3B, right) (104,105). Ligand binding draws the two VFT domains in close proximity, which alters the conformation of the intervening rigid-body to impose rotational shifts of the 7TM bundles that stabilize an active state (106)(107)(108).…”

Section: Class C Gpcrs As a Parallel For Transmission Of Distal Activmentioning

confidence: 99%

Mechanisms of adhesion G protein–coupled receptor activation

Vizurraga

Adhikari

Yeung

et al. 2020

Journal of Biological Chemistry

105

141

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Adhesion G protein coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR Autoproteolysis-Inducing (GAIN) domain that is proximal to the N-terminus of the G protein-coupling seven transmembrane spanning (7TM) bundle. GAIN domain-mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide-agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological-contexts.

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“…In contrast to multi-pass (integral) membrane proteins, where considerable work has been performed, in particular the GPCR class of membrane proteins e.g., [885][886][887][888][889][890][891][892][893][894][895][896][897][898][899] (for review see references: [31,[900][901][902][903]), that are a very hot topic, peripheral and bitopic (single pass) membrane proteins, which constitute 43-45% of transmembrane proteins [883], are underrepresented in MD simulation studies.…”

Section: Other Effects On Lipid Layers-pulmonary Surfactants and Indirect Effect On Membrane Proteinsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Exploring the Activation Mechanism of a Metabotropic Glutamate Receptor Homodimer via Molecular Dynamics Simulation

Cited by 13 publications

References 108 publications

Molecular Mechanisms of Diverse Activation Stimulated by Different Biased Agonists for the β2-Adrenergic Receptor

Molecular Mechanisms of Diverse Activation Stimulated by Different Biased Agonists for the β2-Adrenergic Receptor

Mechanisms of adhesion G protein–coupled receptor activation

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

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