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- EMDB-25586: CryoEM structure of somatostatin receptor 2 in complex with somat... -

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Entry
Database: EMDB / ID: EMD-25586
TitleCryoEM structure of somatostatin receptor 2 in complex with somatostatin-14 and Gi3
Map dataCryoEM structure of SSTR2/Gi3 complex bound to SST14
Sample
  • Complex: Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.
    • Protein or peptide: Somatostatin receptor type 2,Kappa-type opioid receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-3
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Somatostatin-14
    • Protein or peptide: scFv16
  • Ligand: water
Function / homology
Function and homology information


somatostatin signaling pathway / dynorphin receptor activity / response to acrylamide / regulation of saliva secretion / somatostatin receptor activity / MECP2 regulates transcription of neuronal ligands / negative regulation of luteinizing hormone secretion / positive regulation of eating behavior / sensory perception of temperature stimulus / hormone-mediated apoptotic signaling pathway ...somatostatin signaling pathway / dynorphin receptor activity / response to acrylamide / regulation of saliva secretion / somatostatin receptor activity / MECP2 regulates transcription of neuronal ligands / negative regulation of luteinizing hormone secretion / positive regulation of eating behavior / sensory perception of temperature stimulus / hormone-mediated apoptotic signaling pathway / adenylate cyclase-inhibiting opioid receptor signaling pathway / G protein-coupled opioid receptor activity / conditioned place preference / G protein-coupled opioid receptor signaling pathway / peristalsis / positive regulation of dopamine secretion / positive regulation of potassium ion transmembrane transport / sensory perception / maternal behavior / negative regulation of adenylate cyclase activity / neuropeptide binding / receptor serine/threonine kinase binding / response to acidic pH / hyperosmotic response / GTP metabolic process / cellular response to glucocorticoid stimulus / response to steroid hormone / positive regulation of p38MAPK cascade / dopamine receptor signaling pathway / eating behavior / response to starvation / neuronal dense core vesicle / behavioral response to cocaine / regulation of postsynaptic membrane neurotransmitter receptor levels / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of macroautophagy / estrous cycle / Adenylate cyclase inhibitory pathway / GABA-ergic synapse / neuropeptide signaling pathway / response to amino acid / axon terminus / MECP2 regulates neuronal receptors and channels / forebrain development / regulation of cell migration / sensory perception of pain / digestion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cerebellum development / Peptide ligand-binding receptors / response to nutrient / locomotory behavior / cellular response to estradiol stimulus / G protein-coupled receptor binding / PDZ domain binding / cellular response to glucose stimulus / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / response to insulin / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / hormone activity / synaptic vesicle membrane / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / response to estrogen / sensory perception of taste / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity
Similarity search - Function
Somatostatin / Somatostatin/Cortistatin, C-terminal / Somatostatin/Cortistatin family / Kappa opioid receptor / Somatostatin receptor 2 / Somatostatin receptor family / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. ...Somatostatin / Somatostatin/Cortistatin, C-terminal / Somatostatin/Cortistatin family / Kappa opioid receptor / Somatostatin receptor 2 / Somatostatin receptor family / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsRobertson MJ / Skinotis G
Funding support1 items
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, 2021-
Header (metadata) releaseMar 9, 2022-
Map releaseMar 9, 2022-
UpdateMar 30, 2022-
Current statusMar 30, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.633
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.633
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7t10
  • Surface level: 0.633
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25586.png

Downloads & links

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Map

FileDownload / File: emd_25586.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM structure of SSTR2/Gi3 complex bound to SST14
Voxel sizeX=Y=Z: 0.8521 Å
Density
Contour LevelBy AUTHOR: 0.633 / Movie #1: 0.633
Minimum - Maximum-4.3651137 - 6.825321
Average (Standard dev.)-2.6759497e-05 (±0.10269163)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 306.756 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.85210.85210.8521
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z306.756306.756306.756
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-4.3656.825-0.000

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Supplemental data

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Sample components

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Entire : Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.

EntireName: Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.
Components
  • Complex: Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.
    • Protein or peptide: Somatostatin receptor type 2,Kappa-type opioid receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-3
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Somatostatin-14
    • Protein or peptide: scFv16
  • Ligand: water

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Supramolecule #1: Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.

SupramoleculeName: Somatostatin receptor 2 in complex with Somatostatin-14 and Gi3.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6

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

MacromoleculeName: Somatostatin receptor type 2,Kappa-type opioid receptor
type: protein_or_peptide / ID: 1
Details: Somatostatin receptor type 2 with intracellular loop 3 (ICL3) replaced with the ICL3 from the Kappa-type opioid receptor
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.784211 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDAMG QPGNGSAFLL APNRSHAPDH DVENLYFQGM DMADEPLNGS HTWLSIPFDL NGSVVSTNTS NQTEPYYDLT SNAVLTFIY FVVCIIGLCG NTLVIYVILR YAKMKTITNI YILNLAIADE LFMLGLPFLA MQVALVHWPF GKAICRVVMT V DGINQFTS ...String:
DYKDDDDAMG QPGNGSAFLL APNRSHAPDH DVENLYFQGM DMADEPLNGS HTWLSIPFDL NGSVVSTNTS NQTEPYYDLT SNAVLTFIY FVVCIIGLCG NTLVIYVILR YAKMKTITNI YILNLAIADE LFMLGLPFLA MQVALVHWPF GKAICRVVMT V DGINQFTS IFCLTVMSID RYLAVVHPIK SAKWRRPRTA KMITMAVWGV SLLVILPIMI YAGLRSNQWG RSSCTINWPG ES GAWYTGF IIYTFILGFL VPLTIICLCY LFIIIKVKSV RLLSGSREKD RNLRKVTRMV SIVVAVFIFC WLPFYIFNVS SVS MAISPT PALKGMFDFV VVLTYANSCA NPILYAFLSD NFKKSFQNVL CLVKVSGTDD GERSDSKQDK SRLNETTETQ RTLL NGDLQ TSI

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

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-3
type: protein_or_peptide / ID: 2 / Details: dominant negative / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.584156 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AKEVKLLLLG AGESGKNTIV KQMKIIHEDG YSEDECKQYK VVVYSNTIQS IIAIIRAMG RLKIDFGEAA RADDARQLFV LAGSAEEGVM TPELAGVIKR LWRDGGVQAC FSRSREYQLN DSASYYLNDL D RISQSNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AKEVKLLLLG AGESGKNTIV KQMKIIHEDG YSEDECKQYK VVVYSNTIQS IIAIIRAMG RLKIDFGEAA RADDARQLFV LAGSAEEGVM TPELAGVIKR LWRDGGVQAC FSRSREYQLN DSASYYLNDL D RISQSNYI PTQQDVLRTR VKTTGIVETH FTFKDLYFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTETSIILF LNKKDLFEEK IKRSPLTICY PEYTGSNTYE EAAAYIQCQF EDLNRRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKECGLY

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.671102 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String:
PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #5: Somatostatin-14

MacromoleculeName: Somatostatin-14 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.641909 KDa
SequenceString:
AGCKNFFWKT FTSC

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Macromolecule #6: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.784896 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAHHHHHH HH

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 5 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.04 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 442863

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