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- PDB-9q3l: CryoEM structure of beta2-adrenergic receptor dimer mediated by a... -

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Basic information

Entry
Database: PDB / ID: 9q3l
TitleCryoEM structure of beta2-adrenergic receptor dimer mediated by a biased allosteric modulator in lipid nanodisc
ComponentsBeta-2 adrenergic receptor
KeywordsSIGNALING PROTEIN / GPCR / Adrenergic receptor / Dimer / Molecular glue / Biased allosteric modulator
Function / homology
Function and homology information


beta2-adrenergic receptor activity / positive regulation of mini excitatory postsynaptic potential / AMPA selective glutamate receptor signaling pathway / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / norepinephrine binding / Adrenoceptors / positive regulation of lipophagy / positive regulation of cardiac muscle cell contraction ...beta2-adrenergic receptor activity / positive regulation of mini excitatory postsynaptic potential / AMPA selective glutamate receptor signaling pathway / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / norepinephrine binding / Adrenoceptors / positive regulation of lipophagy / positive regulation of cardiac muscle cell contraction / negative regulation of G protein-coupled receptor signaling pathway / regulation of smooth muscle contraction / adrenergic receptor signaling pathway / response to psychosocial stress / endosome to lysosome transport / positive regulation of glutamate receptor signaling pathway / negative regulation of cardiac muscle cell apoptotic process / potassium channel regulator activity / adenylate cyclase binding / positive regulation of cardiac muscle cell apoptotic process / neuronal dense core vesicle / adenylate cyclase-activating adrenergic receptor signaling pathway / receptor-mediated endocytosis / clathrin-coated endocytic vesicle membrane / cellular response to amyloid-beta / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Cargo recognition for clathrin-mediated endocytosis / positive regulation of cold-induced thermogenesis / amyloid-beta binding / Clathrin-mediated endocytosis / G alpha (s) signalling events / positive regulation of MAPK cascade / cell surface receptor signaling pathway / lysosome / signaling receptor complex / endosome / apical plasma membrane / endosome membrane / Ub-specific processing proteases / protein-containing complex binding / Golgi apparatus / protein homodimerization activity / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Beta 2 adrenoceptor / Adrenoceptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
: / TETRADECANE / EICOSANE / Chem-P0G / Beta-2 adrenergic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsShen, J. / Kobilka, B.K.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35 NS137408 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM083118 United States
American Heart Association25POST1411512 United States
CitationJournal: Nature / Year: 2026
Title: A biased allosteric modulator is a molecular glue for βAR dimerization.
Authors: Jiemin Shen / Teja Nikhil Peddada / Konstantin E Komolov / Francesco De Pascali / Alexander M Garces / Haoqing Wang / Muhammad Ehsan / Pil Seok Chae / Michael T Lerch / Jeffrey L Benovic / ...Authors: Jiemin Shen / Teja Nikhil Peddada / Konstantin E Komolov / Francesco De Pascali / Alexander M Garces / Haoqing Wang / Muhammad Ehsan / Pil Seok Chae / Michael T Lerch / Jeffrey L Benovic / Jun Xu / Brian K Kobilka /
Abstract: Family A G-protein-coupled receptors (GPCRs) are typically described as monomers, yet growing evidence suggests that they can form dimers with distinct signalling properties. However, the mechanisms ...Family A G-protein-coupled receptors (GPCRs) are typically described as monomers, yet growing evidence suggests that they can form dimers with distinct signalling properties. However, the mechanisms and therapeutic potential of such dimerization remain poorly understood. Here we show that AP-7-168, an optimized derivative of a β-arrestin-biased negative allosteric modulator of the β-adrenergic receptor (βAR) that sustains bronchorelaxation in cell and tissue models, functions as a molecular glue to stabilize βAR homodimerization. Cryogenic electron microscopy structures reveal a unique binding mode in which two AP-7-168 molecules pack within a pocket formed by transmembrane helices 3, 4 and 5 of two protomers, stabilizing a dimeric conformation that selectively prevents β-arrestin coupling. In cells, AP-7-168 robustly stabilizes βAR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings identify an allosteric mechanism by which a small molecule biases βAR signalling through dimerization, highlighting ligand-stabilized dimerization as a strategy for GPCR modulation.
History
DepositionAug 18, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2026Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.1Aug 26, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
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Revision 1.2Sep 2, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Sep 2, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-2 adrenergic receptor
B: Beta-2 adrenergic receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,10410
Polymers103,5342
Non-polymers2,5698
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Beta-2 adrenergic receptor / Beta-2 adrenoreceptor / Beta-2 adrenoceptor


Mass: 51767.242 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRB2, ADRB2R, B2AR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07550
#2: Chemical ChemComp-C14 / TETRADECANE


Mass: 198.388 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H30
#3: Chemical ChemComp-LFA / EICOSANE / LIPID FRAGMENT


Mass: 282.547 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H42
#4: Chemical ChemComp-P0G / 8-[(1R)-2-{[1,1-dimethyl-2-(2-methylphenyl)ethyl]amino}-1-hydroxyethyl]-5-hydroxy-2H-1,4-benzoxazin-3(4H)-one


Mass: 370.442 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H26N2O4
#5: Chemical ChemComp-A1CNS / 6-bromo-N~4~-cyclohexyl-N~2~-(3,4-difluorophenyl)quinazoline-2,4-diamine


Mass: 433.292 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H19BrF2N4
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Dimeric beta2-adrenergic receptor bound to a biased allosteric modulator in nanodisc
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 237408 / Symmetry type: POINT

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