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- EMDB-25587: CryoEM structure of somatostatin receptor 2 in complex with Octre... -

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Entry
Database: EMDB / ID: EMD-25587
TitleCryoEM structure of somatostatin receptor 2 in complex with Octreotide and Gi3.
Map dataCryoEM single particle reconstruction of SSTR2/Gi3 complex with octreotide.
Sample
  • Complex: Somatostatin receptor 2 in complex with Octreotide and Gi3.
    • 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: scFv16
    • Protein or peptide: Octreotide
    • Protein or peptide: Somatostatin receptor type 2,Kappa-type opioid receptor
Function / homology
Function and homology information


response to acrylamide / adenylate cyclase-inhibiting opioid receptor signaling pathway / dynorphin receptor activity / regulation of saliva secretion / negative regulation of luteinizing hormone secretion / sensory perception of temperature stimulus / positive regulation of eating behavior / somatostatin receptor activity / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor 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 / sensory perception of temperature stimulus / positive regulation of eating behavior / somatostatin receptor activity / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / peristalsis / positive regulation of dopamine secretion / sensory perception / positive regulation of potassium ion transmembrane transport / negative regulation of adenylate cyclase activity / receptor serine/threonine kinase binding / maternal behavior / conditioned place preference / neuropeptide binding / positive regulation of p38MAPK cascade / GTP metabolic process / cellular response to glucocorticoid stimulus / eating behavior / response to starvation / behavioral response to cocaine / positive regulation of macroautophagy / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / Adenylate cyclase inhibitory pathway / forebrain development / estrous cycle / MECP2 regulates neuronal receptors and channels / axon terminus / sensory perception of pain / T-tubule / cerebellum development / Peptide ligand-binding receptors / sarcoplasmic reticulum / PDZ domain binding / locomotory behavior / response to insulin / response to nicotine / cellular response to estradiol stimulus / G protein-coupled receptor binding / cellular response to glucose stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / response to estrogen / G-protein activation / synaptic vesicle membrane / 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 / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / presynaptic membrane / cellular response to lipopolysaccharide / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events
Similarity search - Function
Somatostatin receptor 2 / Kappa opioid receptor / Somatostatin receptor family / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...Somatostatin receptor 2 / Kappa opioid receptor / Somatostatin receptor family / Opioid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / 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 / 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 / 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 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 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: 0.662
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.662
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7t11
  • Surface level: 0.662
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25587.png

Downloads & links

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Map

FileDownload / File: emd_25587.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM single particle reconstruction of SSTR2/Gi3 complex with octreotide.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 360 pix.
= 306.756 Å		0.85 Å/pix.
x 360 pix.
= 306.756 Å		0.85 Å/pix.
x 360 pix.
= 306.756 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8521 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.662 / Movie #1: 0.662
Minimum - Maximum-4.33491 - 6.394294
Average (Standard dev.)-0.00015385996 (±0.097433865)
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-4.3356.394-0.000

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Supplemental data

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Additional map: Focused refinement on receptor and G alpha I...

Fileemd_25587_additional_1.map
AnnotationFocused refinement on receptor and G alpha I CryoEM single particle reconstruction of SSTR2/Gi3 complex with octreotide.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Somatostatin receptor 2 in complex with Octreotide and Gi3.

EntireName: Somatostatin receptor 2 in complex with Octreotide and Gi3.
Components
  • Complex: Somatostatin receptor 2 in complex with Octreotide and Gi3.
    • 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: scFv16
    • Protein or peptide: Octreotide
    • Protein or peptide: Somatostatin receptor type 2,Kappa-type opioid receptor

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

SupramoleculeName: Somatostatin receptor 2 in complex with Octreotide and Gi3.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-3

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-3
type: protein_or_peptide / ID: 1 / 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 #2: 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: 2 / 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 #3: 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: 3 / 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 #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / 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 #5: Octreotide

MacromoleculeName: Octreotide / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.022263 KDa
SequenceString:
(DPN)CF(DTR)KTC(THO)

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Macromolecule #6: Somatostatin receptor type 2,Kappa-type opioid receptor

MacromoleculeName: Somatostatin receptor type 2,Kappa-type opioid receptor
type: protein_or_peptide / ID: 6
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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridMaterial: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.22 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 281479
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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