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- EMDB-33302: CryoEM structure of the somatostatin receptor 2 (SSTR2) in comple... -

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Entry
Database: EMDB / ID: EMD-33302
TitleCryoEM structure of the somatostatin receptor 2 (SSTR2) in complex with Gi1 and its endogeneous peptide ligand SST-14
Map data
Sample
  • Complex: Complex structure of the somatostatin receptor 2 (SSTR2) in complex with Gi1 and its endogeneous peptide ligand SST-14
    • Protein or peptide: Somatostatin receptor type 2
    • 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: Somatostatin-14
KeywordsG protein-coupled receptor / somatostatin receptor 2 / cryo-EM / SIGNALING PROTEIN
Function / homology
Function and homology information


somatostatin signaling pathway / MECP2 regulates transcription of neuronal ligands / somatostatin receptor activity / hormone-mediated apoptotic signaling pathway / peristalsis / hyperosmotic response / neuropeptide binding / response to acidic pH / response to steroid hormone / cellular response to glucocorticoid stimulus ...somatostatin signaling pathway / MECP2 regulates transcription of neuronal ligands / somatostatin receptor activity / hormone-mediated apoptotic signaling pathway / peristalsis / hyperosmotic response / neuropeptide binding / response to acidic pH / response to steroid hormone / cellular response to glucocorticoid stimulus / response to starvation / neuronal dense core vesicle / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of postsynaptic membrane neurotransmitter receptor levels / response to amino acid / neuropeptide signaling pathway / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / T cell migration / forebrain development / D2 dopamine receptor binding / response to prostaglandin E / digestion / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / response to nutrient / cellular response to forskolin / cerebellum development / regulation of mitotic spindle organization / regulation of cell migration / Peptide ligand-binding receptors / GABA-ergic synapse / PDZ domain binding / Regulation of insulin secretion / cellular response to estradiol stimulus / G protein-coupled receptor binding / positive regulation of cholesterol biosynthetic process / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / hormone activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / 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 / 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 / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / GDP binding / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / 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 / cell-cell signaling / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / cell cortex / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / chemical synaptic transmission / G alpha (s) signalling events / spermatogenesis / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling
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 / 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsWenli Z / Shuo H / Na Q / Wenbo Z / Mengjie L / Dehua Y / Ming-Wei W / Wu B / Zhao Q
Funding support China, 8 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)32161133011 China
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)82121005 China
National Science Foundation (NSF, China)81872915 China
National Science Foundation (NSF, China)82073904 China
National Science Foundation (NSF, China)81773792 China
National Science Foundation (NSF, China)81973373 China
National Science Foundation (NSF, China)21704064 China
CitationJournal: Cell Res / Year: 2022
Title: Structural insights into ligand recognition and selectivity of somatostatin receptors.
Authors: Wenli Zhao / Shuo Han / Na Qiu / Wenbo Feng / Mengjie Lu / Wenru Zhang / Mu Wang / Qingtong Zhou / Shutian Chen / Wei Xu / Juan Du / Xiaojing Chu / Cuiying Yi / Antao Dai / Liaoyuan Hu / ...Authors: Wenli Zhao / Shuo Han / Na Qiu / Wenbo Feng / Mengjie Lu / Wenru Zhang / Mu Wang / Qingtong Zhou / Shutian Chen / Wei Xu / Juan Du / Xiaojing Chu / Cuiying Yi / Antao Dai / Liaoyuan Hu / Michelle Y Shen / Yaping Sun / Qing Zhang / Yingli Ma / Wenge Zhong / Dehua Yang / Ming-Wei Wang / Beili Wu / Qiang Zhao /
Abstract: Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for ...Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.
History
DepositionApr 26, 2022-
Header (metadata) releaseAug 3, 2022-
Map releaseAug 3, 2022-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33302.png

Downloads & links

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Map

FileDownload / File: emd_33302.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 256 pix.
= 267.52 Å		1.05 Å/pix.
x 256 pix.
= 267.52 Å		1.05 Å/pix.
x 256 pix.
= 267.52 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.15239805 - 0.21325974
Average (Standard dev.)0.00001173606 (±0.004043782)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33302_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_33302_half_map_2.map
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Sample components

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Entire : Complex structure of the somatostatin receptor 2 (SSTR2) in compl...

EntireName: Complex structure of the somatostatin receptor 2 (SSTR2) in complex with Gi1 and its endogeneous peptide ligand SST-14
Components
  • Complex: Complex structure of the somatostatin receptor 2 (SSTR2) in complex with Gi1 and its endogeneous peptide ligand SST-14
    • Protein or peptide: Somatostatin receptor type 2
    • 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: Somatostatin-14

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Supramolecule #1: Complex structure of the somatostatin receptor 2 (SSTR2) in compl...

SupramoleculeName: Complex structure of the somatostatin receptor 2 (SSTR2) in complex with Gi1 and its endogeneous peptide ligand SST-14
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Somatostatin receptor type 2

MacromoleculeName: Somatostatin receptor type 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.308605 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: DYKDDDDGAP DMADEPLNGS HTWLSIPFDL NGSVVSTNTS NQTEPYYDLT SNAVLTFIYF VVCIIGLCGN TLVIYVILRY AKMKTITNI YILNLAIADE LFMLGLPFLA MQVALVHWPF GKAICRVVMT VDGINQFTSI FCLTVMSIDR YLAVVHPIKS A KWRRPRTA ...String:
DYKDDDDGAP DMADEPLNGS HTWLSIPFDL NGSVVSTNTS NQTEPYYDLT SNAVLTFIYF VVCIIGLCGN TLVIYVILRY AKMKTITNI YILNLAIADE LFMLGLPFLA MQVALVHWPF GKAICRVVMT VDGINQFTSI FCLTVMSIDR YLAVVHPIKS A KWRRPRTA KMITMAVWGV SLLVILPIMI YAGLRSNQWG RSSCTINWPG ESGAWYTGFI IYTFILGFLV PLTIICLCYL FI IIKVKSS GIRVGSSKRK KSEKKVTRMV SIVVAVFIFC WLPFYIFNVS SVSMAISPTP ALKGMFDFVV VLTYANSCAN PIL YAFLSD NFKKSFQNVL CLVKVSGTDD GERSDSKQDK SRLNETTETQ RTEFLEVLFQ GPWSHPQFEK GGGSGGGSGG SAWS HPQFE K

UniProtKB: Somatostatin receptor type 2

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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: 40.435086 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKTIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKTIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVTAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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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: 38.744371 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
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 LKIWN

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

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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: Insecta environmental sample (insect)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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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

UniProtKB: Somatostatin

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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

Concentration1.0 mg/mL
BufferpH: 7.5
GridMaterial: NICKEL/TITANIUM
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 696255
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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