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- PDB-7ryc: Oxytocin receptor (OTR) bound to oxytocin in complex with a heter... -

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Basic information

Entry
Database: PDB / ID: 7ryc
TitleOxytocin receptor (OTR) bound to oxytocin in complex with a heterotrimeric Gq protein
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Oxytocin
  • Oxytocin receptor
  • scFv16
KeywordsMEMBRANE PROTEIN/NEUROPEPTIDE / HORMONE / GPCR COMPLEX / TRANSMEMBRANE RECEPTOR / OXYTOCIN RECEPTOR / OTR / OT / OXTR / G PROTEIN / OXYTOCIN / VASOTOCIN / MEMBRANE PROTEIN / MEMBRANE PROTEIN-NEUROPEPTIDE complex
Function / homology
Function and homology information


oxytocin receptor activity / positive regulation of hindgut contraction / oxytocin receptor binding / neurohypophyseal hormone activity / maternal aggressive behavior / positive regulation of penile erection / maternal process involved in parturition / positive regulation of uterine smooth muscle contraction / regulation of systemic arterial blood pressure by vasopressin / Vasopressin-like receptors ...oxytocin receptor activity / positive regulation of hindgut contraction / oxytocin receptor binding / neurohypophyseal hormone activity / maternal aggressive behavior / positive regulation of penile erection / maternal process involved in parturition / positive regulation of uterine smooth muscle contraction / regulation of systemic arterial blood pressure by vasopressin / Vasopressin-like receptors / sperm ejaculation / vasopressin receptor activity / negative regulation of urine volume / positive regulation of norepinephrine secretion / grooming behavior / response to genistein / positive regulation of prostaglandin secretion / response to sucrose / response to ether / positive regulation of blood pressure / drinking behavior / neuropeptide hormone activity / maternal behavior / positive regulation of synapse assembly / positive regulation of female receptivity / positive regulation of ossification / response to food / eating behavior / male mating behavior / social behavior / response to electrical stimulus / positive regulation of vasoconstriction / response to retinoic acid / response to cAMP / positive regulation of synaptic transmission / neuronal dense core vesicle / lactation / negative regulation of blood pressure / cellular response to hormone stimulus / response to progesterone / muscle contraction / regulation of heart rate / secretory granule / response to glucocorticoid / response to amphetamine / response to activity / response to cocaine / female pregnancy / response to prostaglandin E / memory / response to peptide hormone / Olfactory Signaling Pathway / heart development / Activation of the phototransduction cascade / terminal bouton / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / response to estradiol / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of cold-induced thermogenesis / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / extracellular vesicle / positive regulation of cytosolic calcium ion concentration / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / Ca2+ pathway / 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 / G alpha (q) signalling events / Ras protein signal transduction / cell surface receptor signaling pathway
Similarity search - Function
Oxytocin receptor / Neurohypophysial hormones, N-terminal Domain / Neurohypophysial hormone / Neurohypophysial hormone, conserved site / Neurohypophysial hormone domain superfamily / Neurohypophysial hormones, C-terminal Domain / Neurohypophysial hormones signature. / Neurohypophysial hormones / Vasopressin receptor / YVTN repeat-like/Quinoprotein amine dehydrogenase ...Oxytocin receptor / Neurohypophysial hormones, N-terminal Domain / Neurohypophysial hormone / Neurohypophysial hormone, conserved site / Neurohypophysial hormone domain superfamily / Neurohypophysial hormones, C-terminal Domain / Neurohypophysial hormones signature. / Neurohypophysial hormones / Vasopressin receptor / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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. / P-loop containing nucleotide triphosphate hydrolases / G-protein beta WD-40 repeat / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Oxytocin-neurophysin 1 / Oxytocin receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsMeyerowitz, J.G. / Robertson, M.J. / Skiniotis, G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32-GM089626 United States
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: The oxytocin signaling complex reveals a molecular switch for cation dependence.
Authors: Justin G Meyerowitz / Michael J Robertson / Ximena Barros-Álvarez / Ouliana Panova / Robert M Nwokonko / Yang Gao / Georgios Skiniotis /
Abstract: Oxytocin (OT) and vasopressin (AVP) are conserved peptide signaling hormones that are critical for diverse processes including osmotic homeostasis, reproduction, lactation and social interaction. OT ...Oxytocin (OT) and vasopressin (AVP) are conserved peptide signaling hormones that are critical for diverse processes including osmotic homeostasis, reproduction, lactation and social interaction. OT acts through the oxytocin receptor (OTR), a magnesium-dependent G protein-coupled receptor that is a therapeutic target for treatment of postpartum hemorrhage, dysfunctional labor and autism. However, the molecular mechanisms that underlie OTR activation by OT and the dependence on magnesium remain unknown. Here we present the wild-type active-state structure of human OTR bound to OT and miniG determined by cryo-EM. The structure reveals a unique activation mechanism adopted by OTR involving both the formation of a Mg coordination complex between OT and the receptor, and disruption of transmembrane helix 7 (TM7) by OT. Our functional assays demonstrate the role of TM7 disruption and provide the mechanism of full agonism by OT and partial agonism by OT analogs. Furthermore, we find that the identity of a single cation-coordinating residue across vasopressin family receptors determines whether the receptor is cation-dependent. Collectively, these results demonstrate how the Mg-dependent OTR is activated by OT, provide essential information for structure-based drug discovery efforts and shed light on the molecular determinants of cation dependence of vasopressin family receptors throughout the animal kingdom.
History
DepositionAug 24, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 30, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 9, 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
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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  • EMDB-24733
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Structure viewerMolecule:
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Assembly

Deposited unit
L: Oxytocin
O: Oxytocin receptor
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,6826
Polymers152,6585
Non-polymers241
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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Guanine nucleotide-binding protein ... , 2 types, 2 molecules DC

#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short


Mass: 36573.531 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)
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37728.152 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

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Protein/peptide / Protein / Antibody / Non-polymers , 4 types, 4 molecules LOE

#1: Protein/peptide Oxytocin


Mass: 1008.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: C-C cyclized nonapeptide / Source: (synth.) Homo sapiens (human) / References: UniProt: P01178
#2: Protein Oxytocin receptor / OT-R


Mass: 49627.074 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: OXTR / Cell line (production host): HEK-293S / Production host: Homo sapiens (human) / References: UniProt: P30559
#5: Antibody scFv16


Mass: 27720.795 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / 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

Component
IDNameTypeEntity IDParent-IDSource
1Oxytocin receptor signaling complex with oxytocin and miniGq and an scFvCOMPLEX#1-#50MULTIPLE SOURCES
2OxytocinCOMPLEX#11SYNTHETIC
3Oxytocin receptorCOMPLEX#21RECOMBINANT
4miniGqCOMPLEX#3-#41RECOMBINANT
5scFv16COMPLEX#51RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
45Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
13Homo sapiens (human)9606
24Spodoptera frugiperda (fall armyworm)7108
35Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
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: -1.8 nm / Nominal defocus min: -0.8 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2.497 sec. / Electron dose: 54.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 40

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameCategory
2SerialEMimage acquisition
7UCSF ChimeraXmodel fitting
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 423703 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingB value: 69.03 / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0068454
ELECTRON MICROSCOPYf_angle_d0.85911531
ELECTRON MICROSCOPYf_dihedral_angle_d17.7532808
ELECTRON MICROSCOPYf_chiral_restr0.0531357
ELECTRON MICROSCOPYf_plane_restr0.0041454

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