Molecular Dynamics Simulations of the Effect of the G-Protein and Diffusible Ligands on the β2-Adrenergic Receptor

Goetz, Angela; Lanig, Harald; Gmeiner, Peter; Clark, Timothy

doi:10.1016/j.jmb.2011.10.015

Cited by 33 publications

(41 citation statements)

References 51 publications

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“…The charges of the inactive- and active-state simulation systems were neutralized by adding 11 and 14 chloride ions, respectively. To carry out MD simulations, the GROMACS package was used as described previously 70 . Briefly, the general AMBER force field (GAFF) 71 was used for PZM21 and the lipids and the AMBER force field ff99SB 72 for the receptor.…”

Section: Methodsmentioning

confidence: 99%

Structure-based discovery of opioid analgesics with reduced side effects

Manglik

Lin

Aryal

et al. 2016

Nature

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Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

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Section: Methodsmentioning

confidence: 99%

Structure-based discovery of opioid analgesics with reduced side effects

Manglik

Lin

Aryal

et al. 2016

Nature

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905

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“…13 Previous simulations of rhodopsin and adrenergic receptors 14–18 have revealed general backbone movements that result from ligand binding, but also suggested some notable differences in the activation mechanism for individual GPCRs. It remains controversial how the various proposed conformational changes are coupled.…”

Section: Introductionmentioning

confidence: 99%

Ligand-Dependent Activation and Deactivation of the Human Adenosine A_2AReceptor

et al. 2013

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G protein-coupled receptors (GPCRs) are membrane proteins with critical functions in cellular signal transduction, representing a primary class of drug targets. Acting by direct binding, many drugs modulate GPCR activity and influence the signaling pathways associated with numerous diseases. However, complete details of ligand-dependent GPCR activation/deactivation are difficult to obtain from experiments. Therefore, it remains unclear how ligands modulate a GPCR’s activity. To elucidate the ligand-dependent activation/deactivation mechanism of the human adenosine A2A receptor (AA2AR), a member of the class A GPCRs, we performed large-scale unbiased molecular dynamics and metadynamics simulations of the receptor embedded in a membrane. At the atomic level, we have observed distinct structural states that resemble the active and inactive states. In particular we noted key structural elements changing in a highly concerted fashion during the conformational transitions, including six conformational states of a tryptophan (Trp2466.48). Our findings agree with a previously proposed view, that during activation, this tryptophan residue undergoes a rotameric transition that may be coupled to a series of coherent conformational changes, resulting in the opening of the G protein-binding site. Further, metadynamics simulations provide quantitative evidence for this mechanism, suggesting how ligand binding shifts the equilibrium between the active and inactive states. Our analysis also proposes that a few specific residues are associated with agonism/antagonism, affinity and selectivity, and suggests that the ligand-binding pocket can be thought of as having three distinct regions, providing dynamic features for structure-based design. Additional simulations with AA2AR bound to a novel ligand are consistent with our proposed mechanism. Generally, our study provides insights into the ligand-dependent AA2AR activation/deactivation in addition to what has been found in crystal structures. These results should aid in the discovery of more effective and selective GPCR ligands.

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“…The fact that the 7TMRs reach a stable state after this time has been previously observed. [7,8,12] Thus, after embedding these receptors on a lipid bilayer membrane, the original structures obtained were compared with those found after 30 ns of MD simulations. The effects on the structures were very modest, generating values lower than 8.1 Å in the whole structure.…”

Section: Effects Of MD Simulations On Gb 2 Ar Models and Theoretical mentioning

confidence: 99%

“…In addition, we tested the effect of molecular dynamics (MD) on a nanosecond scale with Gb 2 AR models. [7,8] 2. Materials and methods 2.1 Primary sequence analysis and sequence alignment Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β₂adrenoceptor for the selective design of agonists or antagonists

Segura‐Cabrera

García-Pérez

Ciprés-Flores

et al. 2014

Molecular Simulation

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It is well known that guinea pig b 2 adrenoceptors (Gb 2 ARs) and human b 2 adrenoceptors (Hb 2 ARs) have structural similarity. However, only one conformational state of Gb 2 ARs has been studied -the putative inactive state. As adrenoceptors have a repertoire of conformations, and there is evidence that a certain conformation is stabilised as a ligand approaches, the aim of this study was to build four models of Gb 2 ARs by using putative active/inactive Hb 2 AR conformers as a template. We evaluated the accuracy of these models in regard to the binding mode and affinity values of a set of known b 2 AR ligands through docking and molecular dynamics simulations. During docking simulations, ligands reached Gb 2 AR sites similar to those reported for Hb 2 ARs. The greatest differences between conformational states were found in the domains (TM5 and TM6) previously suggested as being key to ligand recognition. The coefficients of determination between experimental and calculated affinity values were near to but less than 0.66 in all cases. The highest values were for agonists on the active models and antagonists on the inactive model. The four Gb 2 AR models proved useful for analysing agonist/antagonist activity. The results suggest that the selection of an adequate model is dependent on the intrinsic activity of a given ligand.

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Molecular Dynamics Simulations of the Effect of the G-Protein and Diffusible Ligands on the β2-Adrenergic Receptor

Cited by 33 publications

References 51 publications

Structure-based discovery of opioid analgesics with reduced side effects

Structure-based discovery of opioid analgesics with reduced side effects

Ligand-Dependent Activation and Deactivation of the Human Adenosine A_2AReceptor

Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β₂adrenoceptor for the selective design of agonists or antagonists

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Molecular Dynamics Simulations of the Effect of the G-Protein and Diffusible Ligands on the β2-Adrenergic Receptor

Cited by 33 publications

References 51 publications

Structure-based discovery of opioid analgesics with reduced side effects

Structure-based discovery of opioid analgesics with reduced side effects

Ligand-Dependent Activation and Deactivation of the Human Adenosine A2AReceptor

Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β2adrenoceptor for the selective design of agonists or antagonists

Contact Info

Product

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Ligand-Dependent Activation and Deactivation of the Human Adenosine A_2AReceptor

Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β₂adrenoceptor for the selective design of agonists or antagonists