An allosteric modulator binds to a conformational hub in the β2 adrenergic receptor

Liu, Xiangyu; Kaindl, Jonas; Korczynska, Magdalena; Stößel, Anne; Dengler, Daniela G.; Stanek, Markus; Hübner, Harald; Clark, Mary Jo; Mahoney, Jake; Matt, Rachel A.; Xu, Xinyu; Hirata, Kunio; Shoichet, Brian K.; Sunahara, Roger K.; Kobilka, Brian K.; Gmeiner, Peter

doi:10.1038/s41589-020-0549-2

Cited by 60 publications

(75 citation statements)

References 54 publications

(68 reference statements)

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“…There have been three more complex structures of allosteric modulators at lipidic interface since October 2018, all obtained by crystallography. Two are β 2 AR, with a NAM AS408 (PDB code: 6OBA 180 ) or a PAM Cmpd-6FA (PDB code: 6N48 181 ). Both allosteric modulators bind to the LOW345 site (Fig.…”

Section: Allosteric Modulationmentioning

confidence: 99%

G protein-coupled receptors: structure- and function-based drug discovery

Yang

Zhou

Labroska

et al. 2021

Sig Transduct Target Ther

329

280

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As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure–function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.

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Section: Allosteric Modulationmentioning

confidence: 99%

G protein-coupled receptors: structure- and function-based drug discovery

Yang

Zhou

Labroska

et al. 2021

Sig Transduct Target Ther

329

280

View full text Add to dashboard Cite

show abstract

“…Another example is the identification of V206(5.46), S207(5.46), and the PIF motif as a key region for allosteric communication. V206(5.46) and S207(5.46) were shown to interact with a recently discovered negative allosteric modulator that binds in an extrahelical site adjacent to the PIF motif (Liu et al, 2020). Our results do not only illustrate the usefulness of MD combined with data-driven analysis; they allow us to identify potential allosteric sites that can be targeted by ligands, and reveal that, against our expectations, signaling hotspots near the NPxxY motif, far away from the orthosteric site, experience the largest ligand-induced conformational heterogeneity.…”

Section: Molecular Basis For Allosteric Transmission From the Orthosteric To The Intracellular Binding Sitementioning

confidence: 99%

Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling

Fleetwood

Carlsson

Delemotte

2021

eLife

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Ligand binding stabilizes different G protein-coupled receptor states via a complex allosteric process that is not completely understood. Here, we have derived free energy landscapes describing activation of the β2 adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics (MD) simulations. These reveal shifts towards active-like states at the G protein binding site for receptors bound to partial and full agonists and that the ligands modulate the conformational ensemble of the receptor by tuning protein microswitches. We indeed find an excellent correlation between the conformation of the microswitches close to the ligand binding site and in the transmembrane region and experimentally reported cAMP signaling responses. Dimensionality reduction further reveals the similarity between the unique conformational states induced by different ligands and examining the output of classifiers highlights two distant hotspots governing agonism on transmembrane helices 5 and 7.

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“…Site 4 was located on the intracellular side, overlapping with the G Protein binding site and also with the region that interacts with the allosteric ligand in PDB structure 5X7D [22]. Site 6 was situated between TM4 and TM5, where the allosteric modulator in PDB structure 6OBA is bound [24]. Site 7 corresponded to the allosteric site in PDB 6N48 [23], also between TM4 and TM5 and close to ICL2.…”

Section: Correlations With δ Allowed the Identification Of Allostericmentioning

confidence: 99%

“…As a representative case study, we investigated the β2 adrenergic receptor (β2AR), a prototypical class A GPCR. Three structures of the β2AR in the presence of allosteric modulators have recently been determined [22][23][24] (Figure 1a-c). Using experimental structures and also ensembles generated by normal mode analysis (NMA) and molecular dynamics (MD) simulations, we verified that allosteric sites in this receptor were correctly identified based on dynamical correlations.…”

Section: Introductionmentioning

confidence: 99%

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

Renault

Giraldo

2020

IJMS

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G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs.

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An allosteric modulator binds to a conformational hub in the β2 adrenergic receptor

Abstract: Reprints and permissions information is available at www.nature.com/reprints.

Cited by 60 publications

References 54 publications

G protein-coupled receptors: structure- and function-based drug discovery

G protein-coupled receptors: structure- and function-based drug discovery

Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

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