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- EMDB-33098: Structure of somatostatin receptor 2 bound with SST14. -

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Entry
Database: EMDB / ID: EMD-33098
TitleStructure of somatostatin receptor 2 bound with SST14.
Map dataCryo-EM density map of SST14 bound SSTR2-DNGi complex.
Sample
  • Complex: The endogenous ligand SST14-bound somatostatin receptor 2 and Gi heterotrimer complex.
    • Protein or peptide: Somatostatin receptor type 2,LargeBit
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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: Somatostatin-14
Function / homology
Function and homology information


somatostatin signaling pathway / MECP2 regulates transcription of neuronal ligands / somatostatin receptor activity / hormone-mediated apoptotic signaling pathway / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / peristalsis / Activation of the phototransduction cascade / response to acidic pH ...somatostatin signaling pathway / MECP2 regulates transcription of neuronal ligands / somatostatin receptor activity / hormone-mediated apoptotic signaling pathway / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / peristalsis / Activation of the phototransduction cascade / response to acidic pH / hyperosmotic response / neuropeptide binding / cellular response to glucocorticoid stimulus / response to steroid hormone / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / : / G alpha (q) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (i) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / response to starvation / neuronal dense core vesicle / regulation of postsynaptic membrane neurotransmitter receptor levels / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuropeptide signaling pathway / response to amino acid / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / GABA-ergic synapse / cellular response to forskolin / forebrain development / regulation of mitotic spindle organization / digestion / regulation of cell migration / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cerebellum development / Peptide ligand-binding receptors / response to nutrient / cellular response to estradiol stimulus / Regulation of insulin secretion / G protein-coupled receptor binding / PDZ domain binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / hormone activity / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / GDP binding / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / cell-cell signaling / cell cortex / midbody / G alpha (i) signalling events / spermatogenesis / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / chemical synaptic transmission / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / neuron projection / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / lysosomal membrane / cell division / GTPase activity
Similarity search - Function
Somatostatin / Somatostatin/Cortistatin, C-terminal / Somatostatin/Cortistatin family / Somatostatin receptor 2 / Somatostatin receptor family / 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 ...Somatostatin / Somatostatin/Cortistatin, C-terminal / Somatostatin/Cortistatin family / Somatostatin receptor 2 / Somatostatin receptor family / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / 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
Somatostatin receptor type 2 / Somatostatin / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others) / Bos taurus (cattle) / Rattus (rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsBo Q / Yang F / Li YG / Meng XY / Zhang HH / Zhou YX / Ling SL / Sun DM / Lv P / Liu L ...Bo Q / Yang F / Li YG / Meng XY / Zhang HH / Zhou YX / Ling SL / Sun DM / Lv P / Liu L / Shi P / Tian CL
Funding support China, 1 items
OrganizationGrant numberCountry
Other government China
CitationJournal: Cell Discov / Year: 2022
Title: Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues.
Authors: Qing Bo / Fan Yang / Yingge Li / Xianyu Meng / Huanhuan Zhang / Yingxin Zhou / Shenglong Ling / Demeng Sun / Pei Lv / Lei Liu / Pan Shi / Changlin Tian /
Abstract: The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two ...The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between β-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q102, N276, and F294 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.
History
DepositionMar 19, 2022-
Header (metadata) releaseAug 31, 2022-
Map releaseAug 31, 2022-
UpdateAug 31, 2022-
Current statusAug 31, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33098.png

Downloads & links

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Map

FileDownload / File: emd_33098.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM density map of SST14 bound SSTR2-DNGi complex.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 200 pix.
= 214. Å		1.07 Å/pix.
x 200 pix.
= 214. Å		1.07 Å/pix.
x 200 pix.
= 214. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-3.5577114 - 5.98035
Average (Standard dev.)0.0019217309 (±0.13243695)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 214.00002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM half map A of SST14 bound SSTR2-DNGi complex.

Fileemd_33098_half_map_1.map
AnnotationCryo-EM half map A of SST14 bound SSTR2-DNGi complex.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM half map B of SST14 bound SSTR2-DNGi complex.

Fileemd_33098_half_map_2.map
AnnotationCryo-EM half map B of SST14 bound SSTR2-DNGi complex.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The endogenous ligand SST14-bound somatostatin receptor 2 and Gi ...

EntireName: The endogenous ligand SST14-bound somatostatin receptor 2 and Gi heterotrimer complex.
Components
  • Complex: The endogenous ligand SST14-bound somatostatin receptor 2 and Gi heterotrimer complex.
    • Protein or peptide: Somatostatin receptor type 2,LargeBit
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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: Somatostatin-14

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Supramolecule #1: The endogenous ligand SST14-bound somatostatin receptor 2 and Gi ...

SupramoleculeName: The endogenous ligand SST14-bound somatostatin receptor 2 and Gi heterotrimer complex.
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Somatostatin receptor type 2,LargeBit

MacromoleculeName: Somatostatin receptor type 2,LargeBit / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 63.274395 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKGSGSHH HHHHHHHHLE VLFQGPMDMA DEPLNGSHTW LSIPFDLNGS VVSTNTSNQT EPYYDLTSN AVLTFIYFVV CIIGLCGNTL VIYVILRYAK MKTITNIYIL NLAIADELFM LGLPFLAMQV ALVHWPFGKA I CRVVMTVD ...String:
MKTIIALSYI FCLVFADYKD DDDKGSGSHH HHHHHHHHLE VLFQGPMDMA DEPLNGSHTW LSIPFDLNGS VVSTNTSNQT EPYYDLTSN AVLTFIYFVV CIIGLCGNTL VIYVILRYAK MKTITNIYIL NLAIADELFM LGLPFLAMQV ALVHWPFGKA I CRVVMTVD GINQFTSIFC LTVMSIDRYL AVVHPIKSAK WRRPRTAKMI TMAVWGVSLL VILPIMIYAG LRSNQWGRSS CT INWPGES GAWYTGFIIY TFILGFLVPL TIICLCYLFI IIKVKSSGIR VGSSKRKKSE KKVTRMVSIV VAVFIFCWLP FYI FNVSSV SMAISPTPAL KGMFDFVVVL TYANSCANPI LYAFLSDNFK KSFQNVLCLV KVSGTDDGER SDSKQDKSRL NETT ETQRT VFTLEDFVGD WEQTAAYNLD QVLEQGGVSS LLQNLAVSVT PIQRIVRSGE NALKIDIHVI IPYEGLSADQ MAQIE EVFK VVYPVDDHHF KVILPYGTLV IDGVTPNMLN YFGRPYEGIA VFDGKKITVT GTLWNGNKII DERLITPDGS MLFRVT INS

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Macromolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.472082 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

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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: Bos taurus (cattle)
Molecular weightTheoretical: 38.975578 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String:
MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWNGSS

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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: Bos taurus (cattle)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #5: ScFv16

MacromoleculeName: ScFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus (rat)
Molecular weightTheoretical: 32.768484 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFDVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSSG G GGSGGGGS ...String:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFDVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSSG G GGSGGGGS GGGGSSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELVD ENLYFQGASH HHHHHHH

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Macromolecule #6: Somatostatin-14

MacromoleculeName: Somatostatin-14 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.641909 KDa
SequenceString:
AGCKNFFWKT FTSC

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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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: AlphaFold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 457712
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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