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- PDB-9pqd: Locally-refined structure of alpha2a adrenergic receptor in compl... -

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Basic information

Entry
Database: PDB / ID: 9pqd
TitleLocally-refined structure of alpha2a adrenergic receptor in complex with Go heterotrimer, scFv16, and compound Z7149
ComponentsAlpha-2A adrenergic receptor
KeywordsMEMBRANE PROTEIN / GPCR / Complex / Drug / Small Molecule / Polypharmacology
Function / homology
Function and homology information


negative regulation of uterine smooth muscle contraction / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha-2C adrenergic receptor binding / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of epinephrine secretion ...negative regulation of uterine smooth muscle contraction / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha-2C adrenergic receptor binding / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of epinephrine secretion / heterotrimeric G-protein binding / negative regulation of calcium ion-dependent exocytosis / Surfactant metabolism / positive regulation of potassium ion transport / dopaminergic synapse / thermoception / fear response / thioesterase binding / negative regulation of insulin secretion involved in cellular response to glucose stimulus / norepinephrine binding / positive regulation of membrane protein ectodomain proteolysis / Adrenoceptors / response to alcohol / intestinal absorption / adrenergic receptor signaling pathway / positive regulation of wound healing / response to morphine / negative regulation of calcium ion transport / negative regulation of lipid catabolic process / regulation of vasoconstriction / positive regulation of epidermal growth factor receptor signaling pathway / cellular response to hormone stimulus / Rho protein signal transduction / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic active zone membrane / presynaptic modulation of chemical synaptic transmission / axon terminus / guanyl-nucleotide exchange factor activity / positive regulation of cytokine production / female pregnancy / negative regulation of insulin secretion / platelet activation / postsynaptic density membrane / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / vasodilation / GABA-ergic synapse / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / glucose homeostasis / actin cytoskeleton organization / G alpha (i) signalling events / basolateral plasma membrane / Ras protein signal transduction / DNA replication / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / positive regulation of cell migration / G protein-coupled receptor signaling pathway / protein heterodimerization activity / neuronal cell body / positive regulation of cell population proliferation / protein kinase binding / glutamatergic synapse / protein homodimerization activity / plasma membrane / cytoplasm
Similarity search - Function
Alpha 2A 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
: / Alpha-2A adrenergic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsSrinivasan, K. / Wu, Y. / Billesboelle, C. / Kim, J.Y. / Manglik, A. / Shoichet, B.K.
Funding support United States, 2items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-19-2-0020 United States
Department of Health & Human Services (HHS)1AY1AX000035 United States
CitationJournal: J Med Chem / Year: 2026
Title: Large Library Docking for Polypharmacology.
Authors: Yujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S ...Authors: Yujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S Radchenko / Ramona M Rodriguiz / Yurii S Moroz / John J Irwin / Peter Gmeiner / Christian Billesboelle / Bryan L Roth / Allan I Basbaum / Aashish Manglik / William C Wetsel / Brian K Shoichet /
Abstract: Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the ...Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (α/SERT, MOR/SERT, and α/MOR), we sought analgesic compounds. Both the α/SERT and SERT/MOR campaigns led to dual binders with low μM to high nM activities with high hit rates; tetrahydropyridines from the α/SERT campaign were also active against 5-HT. However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent α/SERT compound (') was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT activities. This study reveals both advantages and challenges of docking for polypharmacology.
History
DepositionJul 22, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 20, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Mar 4, 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 / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Alpha-2A adrenergic receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,8562
Polymers53,6441
Non-polymers2121
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Alpha-2A adrenergic receptor / Alpha-2 adrenergic receptor subtype C10 / Alpha-2A adrenoreceptor / Alpha-2A adrenoceptor / Alpha-2AAR


Mass: 53643.855 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRA2A, ADRA2R, ADRAR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08913
#2: Chemical ChemComp-A1CIZ / (6M)-1-methyl-6-(1,2,5,6-tetrahydropyridin-3-yl)-1H-indole


Mass: 212.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16N2 / 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: Alpha2a adrenergic receptor in complex with Go heterotrimer, scFv16, and compound Z7149
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: 7.5
Details: Buffer was supplemented with 0.01 mM compound Z7149
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHepesC8H18N2O4S1
2100 mMSodium chlorideNaCl1
30.0075 % w/vLMNGC47H88O221
40.0025 % w/vGDNC56H92O251
50.001 % w/vCHSC31H50O41
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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: 1600 nm / Nominal defocus min: 800 nm
Image recordingAverage exposure time: 2 sec. / Electron dose: 47.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
12cryoSPARC3D reconstruction
13PHENIX1.21.2_5419model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38025 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7EJ8

7ej8


Pdb chain-ID: D / Accession code: 7EJ8 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.29 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042218
ELECTRON MICROSCOPYf_angle_d0.6193020
ELECTRON MICROSCOPYf_dihedral_angle_d10.127300
ELECTRON MICROSCOPYf_chiral_restr0.042353
ELECTRON MICROSCOPYf_plane_restr0.004357

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