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- PDB-7ran: 5-HT2AR bound to a novel agonist in complex with a mini-Gq protei... -

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Basic information

Entry
Database: PDB / ID: 7ran
Title5-HT2AR bound to a novel agonist in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • 5-hydroxytryptamine receptor 2A
  • G protein subunit q (Gi2-mini-Gq chimera)
  • single-chain variable fragment 16 (scFv16)
KeywordsMEMBRANE PROTEIN / 5-HT2A receptor / serotonin receptor / G protein / GPCR / novel agonist / cryoEM
Function / homology
Function and homology information


protein localization to cytoskeleton / positive regulation of heat generation / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / cell body fiber / phospholipase C-activating serotonin receptor signaling pathway ...protein localization to cytoskeleton / positive regulation of heat generation / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / cell body fiber / phospholipase C-activating serotonin receptor signaling pathway / artery smooth muscle contraction / Serotonin receptors / serotonin receptor activity / positive regulation of cytokine production involved in immune response / G protein-coupled serotonin receptor activity / sensitization / serotonin receptor signaling pathway / neurotransmitter receptor activity / urinary bladder smooth muscle contraction / serotonin binding / positive regulation of platelet aggregation / negative regulation of synaptic transmission, glutamatergic / positive regulation of DNA biosynthetic process / temperature homeostasis / positive regulation of vasoconstriction / detection of temperature stimulus involved in sensory perception of pain / regulation of dopamine secretion / negative regulation of potassium ion transport / protein tyrosine kinase activator activity / positive regulation of execution phase of apoptosis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of fat cell differentiation / behavioral response to cocaine / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / positive regulation of glycolytic process / dendritic shaft / glycolytic process / caveola / memory / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / intracellular calcium ion homeostasis / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / positive regulation of inflammatory response / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / positive regulation of neuron apoptotic process / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / virus receptor activity / presynaptic membrane / GTPase binding / Ca2+ pathway / cytoplasmic vesicle / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / Ras protein signal transduction / postsynaptic membrane / Extra-nuclear estrogen signaling / cell population proliferation
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily ...5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / P-loop containing nucleotide triphosphate hydrolases / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-3IQ / 5-hydroxytryptamine receptor 2A / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.45 Å
AuthorsBarros-Alvarez, X. / Kim, K. / Panova, O. / Roth, B.L. / Skiniotis, G.
Funding support United States, 1items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA) United States
CitationJournal: Nature / Year: 2022
Title: Bespoke library docking for 5-HT receptor agonists with antidepressant activity.
Authors: Anat Levit Kaplan / Danielle N Confair / Kuglae Kim / Ximena Barros-Álvarez / Ramona M Rodriguiz / Ying Yang / Oh Sang Kweon / Tao Che / John D McCorvy / David N Kamber / James P Phelan / ...Authors: Anat Levit Kaplan / Danielle N Confair / Kuglae Kim / Ximena Barros-Álvarez / Ramona M Rodriguiz / Ying Yang / Oh Sang Kweon / Tao Che / John D McCorvy / David N Kamber / James P Phelan / Luan Carvalho Martins / Vladimir M Pogorelov / Jeffrey F DiBerto / Samuel T Slocum / Xi-Ping Huang / Jain Manish Kumar / Michael J Robertson / Ouliana Panova / Alpay B Seven / Autumn Q Wetsel / William C Wetsel / John J Irwin / Georgios Skiniotis / Brian K Shoichet / Bryan L Roth / Jonathan A Ellman /
Abstract: There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally. Efforts have focused on readily synthesizable molecules, ...There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT receptor (5-HTR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT or the 5-HT receptors. Structure-based optimization led to the 5-HTR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HTR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HTR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HTR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.
History
DepositionJul 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2022Provider: repository / Type: Initial release
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Revision 1.0Jul 6, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Oct 12, 2022Group: Database references / Category: citation / citation_author
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Revision 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
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Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 2A
B: G protein subunit q (Gi2-mini-Gq chimera)
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: single-chain variable fragment 16 (scFv16)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,4046
Polymers142,1895
Non-polymers2141
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein 5-hydroxytryptamine receptor 2A / 5-HT-2 / 5-HT-2A / Serotonin receptor 2A


Mass: 38274.285 Da / Num. of mol.: 1 / Fragment: UNP residues 66-404
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR2A, HTR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223
#2: Protein G protein subunit q (Gi2-mini-Gq chimera)


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD

#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Non-polymers , 2 types, 2 molecules E

#5: Antibody single-chain variable fragment 16 (scFv16)


Mass: 30552.234 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-3IQ / (3R)-3-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,2,3,6-tetrahydropyridin-1-ium


Mass: 214.286 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16N3 / Feature type: SUBJECT OF INVESTIGATION

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Details

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: 5-HT2AR bound to a tetrahydropyridine agonist (R-69) in complex with heterotrimeric mini-Gq protein and single-chain variable fragment (scFv16)
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 17.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE

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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 / Calibrated magnification: 57050 X / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60.01 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategoryDetails
1RELION3.1particle selection
2SerialEMimage acquisition
4RELION3.1CTF correction
8PHENIXmodel refinement
10RELIONinitial Euler assignment3.1
11RELIONfinal Euler assignment3.1
13RELION3D reconstruction3.1
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88393 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038726
ELECTRON MICROSCOPYf_angle_d0.53211858
ELECTRON MICROSCOPYf_dihedral_angle_d4.3271220
ELECTRON MICROSCOPYf_chiral_restr0.0421371
ELECTRON MICROSCOPYf_plane_restr0.0041522

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