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- PDB-9dnm: Structure of rat beta-arrestin 1 bound to allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 9dnm
TitleStructure of rat beta-arrestin 1 bound to allosteric inhibitor
Components
  • Beta-arrestin-1,Soluble cytochrome b562
  • anti-BRIL Fab Heavy chain
  • anti-BRIL Fab Light chain
KeywordsSIGNALING PROTEIN/Immune System / GPCR signaling / arrestin / allostery / SIGNALING PROTEIN / SIGNALING PROTEIN-Immune System complex
Function / homology
Function and homology information


V2 vasopressin receptor binding / alpha-1A adrenergic receptor binding / follicle-stimulating hormone receptor binding / TGFBR3 regulates TGF-beta signaling / sensory perception of touch / G alpha (s) signalling events / alpha-1B adrenergic receptor binding / regulation of inositol trisphosphate biosynthetic process / follicle-stimulating hormone signaling pathway / protein phosphorylated amino acid binding ...V2 vasopressin receptor binding / alpha-1A adrenergic receptor binding / follicle-stimulating hormone receptor binding / TGFBR3 regulates TGF-beta signaling / sensory perception of touch / G alpha (s) signalling events / alpha-1B adrenergic receptor binding / regulation of inositol trisphosphate biosynthetic process / follicle-stimulating hormone signaling pathway / protein phosphorylated amino acid binding / Lysosome Vesicle Biogenesis / angiotensin receptor binding / Golgi Associated Vesicle Biogenesis / AP-2 adaptor complex binding / Ub-specific processing proteases / MAP2K and MAPK activation / Cargo recognition for clathrin-mediated endocytosis / clathrin adaptor activity / Clathrin-mediated endocytosis / negative regulation of interleukin-8 production / regulation of G protein-coupled receptor signaling pathway / G protein-coupled receptor internalization / arrestin family protein binding / cysteine-type endopeptidase inhibitor activity involved in apoptotic process / Thrombin signalling through proteinase activated receptors (PARs) / response to morphine / mitogen-activated protein kinase kinase binding / clathrin binding / stress fiber assembly / positive regulation of Rho protein signal transduction / pseudopodium / negative regulation of interleukin-6 production / positive regulation of receptor internalization / negative regulation of Notch signaling pathway / phototransduction / positive regulation of insulin secretion involved in cellular response to glucose stimulus / clathrin-coated pit / insulin-like growth factor receptor binding / negative regulation of protein ubiquitination / GTPase activator activity / nuclear estrogen receptor binding / positive regulation of protein ubiquitination / phosphoprotein binding / G protein-coupled receptor binding / electron transport chain / negative regulation of ERK1 and ERK2 cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / endocytosis / positive regulation of protein phosphorylation / protein transport / ubiquitin-dependent protein catabolic process / cytoplasmic vesicle / regulation of apoptotic process / basolateral plasma membrane / molecular adaptor activity / dendritic spine / proteasome-mediated ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic process / transmembrane transporter binding / postsynaptic membrane / transcription coactivator activity / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / endosome / positive regulation of MAPK cascade / postsynaptic density / protein ubiquitination / G protein-coupled receptor signaling pathway / iron ion binding / response to xenobiotic stimulus / signaling receptor binding / positive regulation of cell population proliferation / heme binding / ubiquitin protein ligase binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal ...Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Immunoglobulin E-set
Similarity search - Domain/homology
Chem-ODN / Soluble cytochrome b562 / Beta-arrestin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsPakharukova, N. / Kahsai, A.W. / Masoudi, A. / Lefkowitz, R.J.
Funding support United States, France, European Union, 6items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL016037 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)T32HL007101 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL16037-45S1 United States
Human Frontier Science Program (HFSP)LT000174/2018 France
European Molecular Biology Organization (EMBO)ALTF 1071-2017European Union
CitationJournal: bioRxiv / Year: 2025
Title: Small-molecule modulation of β-arrestins.
Authors: Alem W Kahsai / Natalia Pakharukova / Henry Y Kwon / Kunal S Shah / Jason G Liang-Lin / Caroline T Del Real / Paul J Shim / Mason A Lee / Van A Ngo / Bowie N Shreiber / Samuel Liu / Allison ...Authors: Alem W Kahsai / Natalia Pakharukova / Henry Y Kwon / Kunal S Shah / Jason G Liang-Lin / Caroline T Del Real / Paul J Shim / Mason A Lee / Van A Ngo / Bowie N Shreiber / Samuel Liu / Allison M Schwalb / Emmanuel F Espinoza / Brittany N Thomas / Cal A Kunzle / Jeffrey S Smith / Jialu Wang / Jihee Kim / Xingdong Zhang / Howard A Rockman / Alex R B Thomsen / Lindsay A M Rein / Lei Shi / Seungkirl Ahn / Ali Masoudi / Robert J Lefkowitz
Abstract: β-arrestins are multifunctional regulators of G protein-coupled receptor (GPCR) signaling, orchestrating diverse downstream signaling events and physiological responses across the vast GPCR ...β-arrestins are multifunctional regulators of G protein-coupled receptor (GPCR) signaling, orchestrating diverse downstream signaling events and physiological responses across the vast GPCR superfamily. While GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GRKs, comparable chemical tools to study β-arrestins remain lacking. Here, we report the discovery of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical, and structural analyses. These inhibitors disrupt β-arrestin-engagement with agonist-activated GPCRs, impairing desensitization, internalization, and β-arrestin-dependent functions while sparing G protein-receptor coupling. Cryo-EM, MD simulations, and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a cryptic pocket formed by the middle, C-, and lariat loops of β-arrestin1-a critical receptor-binding interface-stabilizing a distinct conformation incompatible with GPCR engagement. Together, these findings provide a mechanistic framework for β-arrestin modulation, introducing transducer-targeted strategies to fine-tune GPCR signaling and guide the development of pathway-specific therapeutics.
History
DepositionSep 17, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.title / _citation.year ..._citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: anti-BRIL Fab Heavy chain
L: anti-BRIL Fab Light chain
A: Beta-arrestin-1,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,2084
Polymers102,8423
Non-polymers3661
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: Antibody anti-BRIL Fab Heavy chain


Mass: 23904.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#2: Antibody anti-BRIL Fab Light chain


Mass: 23209.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Protein Beta-arrestin-1,Soluble cytochrome b562 / Arrestin beta-1 / Cytochrome b-562


Mass: 55727.160 Da / Num. of mol.: 1 / Mutation: M29W, H124I, R128L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Arrb1, cybC / Production host: Escherichia coli (E. coli) / References: UniProt: P29066, UniProt: P0ABE7
#4: Chemical ChemComp-ODN / (1beta,6beta,7beta,8alpha,9beta,10alpha,13alpha,14R,16beta)-1,6,7,14-tetrahydroxy-7,20-epoxykauran-15-one


Mass: 366.449 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H30O6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: Beta-arrestin 1 with insertion of soluble cytochrome b562 bound to anti-BRIL Fab
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenConc.: 7.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 57 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
4cryoSPARC4.4.1CTF correction
7Coot0.9.8.3model fitting
8ISOLDEmodel fitting
10PHENIX1.20.1-4487model refinement
14cryoSPARC4.4.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177430 / Symmetry type: POINT
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-IDDetails
11G4M

1g4m

A1G4MA1
26WW2

6ww2

L6WW2L2
36WW2

6ww2

H6WW2H2
46WW2

6ww2

A6WW2A2soluble cytochrome b562 insert

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