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- PDB-7t10: CryoEM structure of somatostatin receptor 2 in complex with somat... -

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Basic information

Entry
Database: PDB / ID: 7t10
TitleCryoEM structure of somatostatin receptor 2 in complex with somatostatin-14 and Gi3
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Somatostatin receptor type 2,Kappa-type opioid receptor
  • Somatostatin-14
  • scFv16
KeywordsMEMBRANE PROTEIN/SIGNALING PROTEIN / GPCR / Receptor / Complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-SIGNALING PROTEIN complex
Function / homology
Function and homology information


somatostatin signaling pathway / response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / MECP2 regulates transcription of neuronal ligands / sensory perception of temperature stimulus / somatostatin receptor activity / hormone-mediated apoptotic signaling pathway ...somatostatin signaling pathway / response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / MECP2 regulates transcription of neuronal ligands / sensory perception of temperature stimulus / somatostatin receptor activity / hormone-mediated apoptotic signaling pathway / positive regulation of eating behavior / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / positive regulation of dopamine secretion / sensory perception / negative regulation of adenylate cyclase activity / response to acidic pH / positive regulation of potassium ion transmembrane transport / receptor serine/threonine kinase binding / maternal behavior / neuropeptide binding / positive regulation of p38MAPK cascade / GTP metabolic process / response to steroid hormone / hyperosmotic response / eating behavior / cellular response to glucocorticoid stimulus / positive regulation of macroautophagy / conditioned place preference / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / response to amino acid / neuronal dense core vesicle / regulation of postsynaptic membrane neurotransmitter receptor levels / estrous cycle / behavioral response to cocaine / Adenylate cyclase inhibitory pathway / MECP2 regulates neuronal receptors and channels / digestion / axon terminus / response to nutrient / sensory perception of pain / T-tubule / regulation of cell migration / Peptide ligand-binding receptors / sarcoplasmic reticulum / response to nicotine / PDZ domain binding / locomotory behavior / cellular response to glucose stimulus / cellular response to estradiol stimulus / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to insulin / hormone activity / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / response to estrogen / 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 / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / synaptic vesicle membrane / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / 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 / cell-cell signaling / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity
Similarity search - Function
Somatostatin / Somatostatin/Cortistatin, C-terminal / Somatostatin/Cortistatin family / Somatostatin receptor 2 / Kappa opioid receptor / Somatostatin receptor family / Opioid receptor / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx ...Somatostatin / Somatostatin/Cortistatin, C-terminal / Somatostatin/Cortistatin family / Somatostatin receptor 2 / Kappa opioid receptor / Somatostatin receptor family / Opioid receptor / 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 / 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 / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-3 / Somatostatin receptor type 2 / Kappa-type opioid receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Somatostatin / 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: 2.5 Å
AuthorsRobertson, M.J. / Skinotis, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Plasticity in ligand recognition at somatostatin receptors.
Authors: Michael J Robertson / Justin G Meyerowitz / Ouliana Panova / Kenneth Borrelli / Georgios Skiniotis /
Abstract: Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Members of the SSTR ...Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Members of the SSTR subfamily, particularly SSTR2, are key drug targets for neuroendocrine neoplasms, with synthetic peptide agonists currently in clinical use. Here, we show the cryogenic-electron microscopy structures of active-state SSTR2 in complex with heterotrimeric G and either the endogenous ligand SST14 or the FDA-approved drug octreotide. Complemented by biochemical assays and molecular dynamics simulations, these structures reveal key details of ligand recognition and receptor activation at SSTRs. We find that SSTR ligand recognition is highly diverse, as demonstrated by ligand-induced conformational changes in ECL2 and substantial sequence divergence across subtypes in extracellular regions. Despite this complexity, we rationalize several known sources of SSTR subtype selectivity and identify an additional interaction for specific binding. These results provide valuable insights for structure-based drug discovery at SSTRs.
History
DepositionNov 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 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 1.2Nov 20, 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

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Structure visualization

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Assembly

Deposited unit
R: Somatostatin receptor type 2,Kappa-type opioid receptor
A: Guanine nucleotide-binding protein G(i) subunit alpha-3
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
P: Somatostatin-14
S: scFv16


Theoretical massNumber of molelcules
Total (without water)161,3276
Polymers161,3276
Non-polymers00
Water905
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 ... , 3 types, 3 molecules ABC

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-3 / G(i) alpha-3


Mass: 40584.156 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, A326S
Source method: isolated from a genetically manipulated source
Details: dominant negative / Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P08754
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37671.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Protein / Protein/peptide / Antibody / Non-polymers , 4 types, 8 molecules RPS

#1: Protein Somatostatin receptor type 2,Kappa-type opioid receptor


Mass: 45784.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Somatostatin receptor type 2 with intracellular loop 3 (ICL3) replaced with the ICL3 from the Kappa-type opioid receptor
Source: (gene. exp.) Homo sapiens (human) / Gene: SSTR2, OPRK1, OPRK / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30874, UniProt: P41145
#5: Protein/peptide Somatostatin-14 / SST-14


Mass: 1641.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P61278
#6: Antibody scFv16


Mass: 27784.896 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)
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O

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Details

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: Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.
Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 1.04 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 442863 / Symmetry type: POINT

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