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- PDB-7y24: Cryo-EM structure of the octreotide-bound SSTR2-miniGo-scFv16 complex -

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Basic information

Entry
Database: PDB / ID: 7y24
TitleCryo-EM structure of the octreotide-bound SSTR2-miniGo-scFv16 complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Octreotide
  • Somatostatin receptor type 2
  • single Fab chain (svFv16)
KeywordsSTRUCTURAL PROTEIN / GPCR / somatostatin receptor / G protein
Function / homology
Function and homology information


somatostatin receptor activity / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / neuropeptide binding / vesicle docking involved in exocytosis / cellular response to glucocorticoid stimulus / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger ...somatostatin receptor activity / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / neuropeptide binding / vesicle docking involved in exocytosis / cellular response to glucocorticoid stimulus / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / postsynaptic modulation of chemical synaptic transmission / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / muscle contraction / Peptide ligand-binding receptors / PDZ domain binding / locomotory behavior / cellular response to estradiol stimulus / negative regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / 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 / 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 / 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 / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / cell body / presynaptic membrane / GTPase binding / Ca2+ pathway / 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 / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / postsynaptic membrane / Extra-nuclear estrogen signaling / cell population proliferation / neuron projection / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / synapse / dendrite / GTP binding / protein-containing complex binding / glutamatergic synapse / signal transduction / extracellular exosome / nucleoplasm / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Somatostatin receptor 2 / Somatostatin receptor family / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit ...Somatostatin receptor 2 / Somatostatin receptor family / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(o) subunit alpha / Somatostatin receptor type 2 / 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: 3.25 Å
AuthorsChen, S. / Zheng, S.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China) China
CitationJournal: Nat Chem Biol / Year: 2023
Title: Molecular basis for the selective G protein signaling of somatostatin receptors.
Authors: Sijia Chen / Xiao Teng / Sanduo Zheng /
Abstract: G protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G ...G protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G protein subtypes. Here we validate that in addition to the well-known G pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the G pathway and show that smaller ligands preferentially activate the G pathway. We further determined cryo-electron microscopy structures of the SSTR2‒G and SSTR2‒G complexes bound to octreotide and SST-14. Structural and functional analysis revealed that G protein selectivity of SSTRs is not only determined by structural elements in the receptor-G protein interface, but also by the conformation of the agonist-binding pocket. Accordingly, smaller ligands fail to stabilize a broader agonist-binding pocket of SSTRs that is required for efficient G coupling but not G coupling. Our studies facilitate the design of drugs with selective G protein signaling to improve therapeutic efficacy.
History
DepositionJun 9, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 19, 2022Provider: repository / Type: Initial release
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Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(o) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: single Fab chain (svFv16)
C: Octreotide
E: Somatostatin receptor type 2


Theoretical massNumber of molelcules
Total (without water)132,4146
Polymers132,4146
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 25056.553 Da / Num. of mol.: 1
Fragment: UNP residues 5-57, UNP residues 182-231, UNP residues 242-354
Mutation: G42N,E43N,A227D,G230D,L250D,I332A,V335I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P09471
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37198.656 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
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6160.126 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 / Protein/peptide / Protein , 3 types, 3 molecules SCE

#4: Antibody single Fab chain (svFv16)


Mass: 26222.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#5: Protein/peptide Octreotide


Mass: 1036.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#6: Protein Somatostatin receptor type 2 / SS-2-R / SS2-R / SS2R / SST2 / SRIF-1


Mass: 36740.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SSTR2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P30874

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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
1complex of SSTR2-miniGo-scFv16 bound with octreotideCOMPLEXall0MULTIPLE SOURCES
2G(o) subunit alphaCOMPLEX#11RECOMBINANT
3G(I)/G(S)/G(T) subunit beta-1, G(I)/G(S)/G(O) subunit gamma-2COMPLEX#2-#41RECOMBINANT
4svFv16, octreotideCOMPLEX#51SYNTHETIC
5Somatostatin receptor type 2COMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Homo sapiens (human)9606HEK293
32Spodoptera frugiperda (fall armyworm)7108
44Homo sapiens (human)9606HEK293
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen 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 / Nominal defocus max: 5000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 687989 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038406
ELECTRON MICROSCOPYf_angle_d0.60411471
ELECTRON MICROSCOPYf_dihedral_angle_d4.4081200
ELECTRON MICROSCOPYf_chiral_restr0.0431355
ELECTRON MICROSCOPYf_plane_restr0.0061453

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