Conformational Basis of G Protein-Coupled Receptor Signaling Versatility

Wingler, Laura M.; Lefkowitz, Robert J.

doi:10.1016/j.tcb.2020.06.002

Cited by 178 publications

(167 citation statements)

References 79 publications

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“…3B. This observation supports the notion that the apo AT1R is normally inactive but the active conformer also exists in its ensemble, which is in line with the basal activity in GPCR [46][47][48] To further elucidate the activation mechanism of AT1R, we focused on the observation of the key residue rearrangements. During GPCR activation, the emergence of residue rearrangements or "micro-switches" is fundamental to TM movement.…”

Section: Markov State Model Revealed a Synergistic Transition Mechanisupporting

confidence: 77%

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Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as novel targets for allosteric drug design

Yang

Chai

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) are the most frequent targets of approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we utilized a combined computational and experimental framework that integrated extensive molecular dynamics simulations, Markov state models, and site-directed mutagenesis for investigating the conformational landscape of activation of the angiotensin II (AngII) type 1 receptor (AT1R), a prototypical class A GPCR. Our findings suggested a synergistic transition mechanism of AT1R activation. Importantly, a key intermediate state was found in the activation pathway. We discovered a novel “cryptic” binding site in the intracellular region of the receptor in the intermediate state. Furthermore, a bioluminescence resonance energy transfer analysis revealed the insensitivity of the endogenous AngII octapeptide agonist in the activation of the downstream Gq signaling and β-arrestin-mediated pathways, upon mutations of the predicted cryptic binding site, thereby suggesting an allosteric regulatory mechanism. Together, these findings not only provide a deeper understanding of AT1R activation at an atomic level, but also open potential avenues for the design of allosteric AT1R modulators. Consequently, this will provide a broad range of applications for GPCR biology, biophysics, and medicinal chemistry.

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Section: Markov State Model Revealed a Synergistic Transition Mechanisupporting

confidence: 77%

“…Notably, intermediate states and active states exist naturally in apo AT1R. This population distribution has been proven in other apo GPCRs as means of basal activity 47,48,68,69 . Thus, agonists select and stabilize the active conformation of GPCRs and promote the binding of transducers.…”

Section: Mutagenesis Confirmed the Predicted Cryptic Binding Sitementioning

confidence: 77%

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as novel targets for allosteric drug design

Yang

Chai

et al. 2020

Preprint

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“…While growing number of structural biology studies characterize molecular nature of specific interactions between a G-protein heterodimer and various GPCRs [ 6 , 60 , 61 ], potential mechanisms coupling the receptors to arrestins remain much more elusive. Recently, however, structures of β-arrestin-1 complexes with neurotensin-1 receptor [ 62 ] and turkey thermostable β 1 -AR [ 63 ] were reported.…”

Section: Discussionmentioning

confidence: 99%

“…Although GPCRs all share characteristic fold of seven transmembrane helices (TM) and correlated molecular mechanisms of signal transduction, they are enormously versatile; unique structural features of an individual GPCR allow precise recognition of defined extracellular stimulus (chemical or physical) and initiate highly specific biochemical response at the intracellular level [ 3 , 4 ]. Functional investigations in recent years unravel a complex nature of signaling phenomenon, extracellular ligand modulation usually leads its receptor to activate a series of distinct signaling events in the cell [ 4 , 5 , 6 ]. In addition to canonical pathways regulated by coupling to a G protein, other G-protein independent signaling can be registered usually associated with arrestin recruitment or direct interactions with cellular kinases [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Ligand—Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors

Jóźwiak

Płazińska

2021

Molecules

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G protein-coupled receptors (GPCRs) are versatile signaling proteins that mediate complex cellular responses to hormones and neurotransmitters. Ligand directed signaling is observed when agonists, upon binding to the same receptor, trigger significantly different configuration of intracellular events. The current work reviews the structurally defined ligand – receptor interactions that can be related to specific molecular mechanisms of ligand directed signaling across different receptors belonging to class A of GPCRs. Recent advances in GPCR structural biology allow for mapping receptors’ binding sites with residues particularly important in recognition of ligands’ structural features that are responsible for biased signaling. Various studies show particular role of specific residues lining the extended ligand binding domains, biased agonists may alternatively affect their interhelical interactions and flexibility what can be translated into intracellular loop rearrangements. Studies on opioid and angiotensin receptors indicate importance of residues located deeper within the binding cavity and direct interactions with receptor residues linking the ortosteric ligand binding site with the intracellular transducer binding domain. Collection of results across different receptors may suggest elements of common molecular mechanisms which are responsible for passing alternative signals from biased agonists.

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“…The diverse stimuli recognized by GPCRs induce conformational changes within the receptor, which activate distinct signalling pathways 2 . As opposed to the large number of GPCRs, the intracellular signalling molecules are less diverse.…”

Section: Introductionmentioning

confidence: 99%

GRK2/3/5/6 knockout: The impact of individual GRKs on arrestin-binding and GPCR regulation

Drube

Haider

Matthees

et al. 2021

Preprint

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G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and represent major drug targets. Upon ligand stimulation, GPCRs activate G proteins and undergo a complex regulation by interaction with GPCR kinases (GRKs) and formation of receptor-arrestin complexes. For many GPCRs, this mechanism triggers receptor desensitisation, internalisation, and possibly a second intracellular signalling wave. Here we created eleven different HEK293 knockout cell clones for GRK2, 3, 5, and 6 individually and in combination. These include four single, two double, four triple, and the quadruple GRK knockout. The statistical evaluation of β-arrestin1/2 interactions for twelve different receptors grouped the tested GPCRs into two main subsets: those for which β-arrestin interaction was mediated by either GRK2, 3, 5, or 6 and those that are mediated by GRK2 or 3 only. Interestingly, the overexpression of specific GRKs was found to induce a robust, ligand-independent β-arrestin interaction with the V2R and AT1R. Finally, using GRK knockout cells, PKC inhibitors, and β-arrestin mutants, we present evidence for differential AT1R-β-arrestin2 complex configurations mediated by selective engagement of PKC, GRK2, or GRK6. We anticipate our novel GRK-knockout platform to facilitate the elucidation of previously unappreciated details of GRK-specific GPCR regulation and β-arrestin complex formation.

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Conformational Basis of G Protein-Coupled Receptor Signaling Versatility

Cited by 178 publications

References 79 publications

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as novel targets for allosteric drug design

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as novel targets for allosteric drug design

Structural Insights into Ligand—Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors

GRK2/3/5/6 knockout: The impact of individual GRKs on arrestin-binding and GPCR regulation

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