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- EMDB-33304: CryoEM structure of somatostatin receptor 4 (SSTR4) with Gi1 and ... -

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Entry
Database: EMDB / ID: EMD-33304
TitleCryoEM structure of somatostatin receptor 4 (SSTR4) with Gi1 and J-2156
Map data
Sample
  • Complex: Complex structure of somatostatin receptor 4 (SSTR4) with Gi and J-2156
    • Protein or peptide: Somatostatin receptor type 4
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: single chain variable fragment of antibody
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Ligand: (2~{S})-2-[[(2~{S})-4-azanyl-2-[(4-methylnaphthalen-1-yl)sulfonylamino]butanoyl]amino]-3-phenyl-propanimidic acid
Function / homology
Function and homology information


somatostatin receptor activity / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of arachidonic acid secretion / neuropeptide binding / cellular response to glucocorticoid stimulus / plasma membrane => GO:0005886 / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / neuropeptide signaling pathway ...somatostatin receptor activity / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of arachidonic acid secretion / neuropeptide binding / cellular response to glucocorticoid stimulus / plasma membrane => GO:0005886 / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / neuropeptide signaling pathway / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / forebrain development / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / peptide binding / 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 / 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / 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 / 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 / cell migration / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / neuron projection / cell cycle / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / negative regulation of cell population proliferation / GTPase activity / centrosome / synapse / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Somatostatin receptor 4 / Somatostatin receptor family / 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 ...Somatostatin receptor 4 / Somatostatin receptor family / 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
Somatostatin receptor type 4 / 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 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-
UpdateAug 17, 2022-
Current statusAug 17, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33304.png

Downloads & links

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Map

FileDownload / File: emd_33304.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.19749762 - 0.25723502
Average (Standard dev.)1.7855992e-06 (±0.0050810534)
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: #2

Fileemd_33304_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33304_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Complex structure of somatostatin receptor 4 (SSTR4) with Gi and ...

EntireName: Complex structure of somatostatin receptor 4 (SSTR4) with Gi and J-2156
Components
  • Complex: Complex structure of somatostatin receptor 4 (SSTR4) with Gi and J-2156
    • Protein or peptide: Somatostatin receptor type 4
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: single chain variable fragment of antibody
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Ligand: (2~{S})-2-[[(2~{S})-4-azanyl-2-[(4-methylnaphthalen-1-yl)sulfonylamino]butanoyl]amino]-3-phenyl-propanimidic acid

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Supramolecule #1: Complex structure of somatostatin receptor 4 (SSTR4) with Gi and ...

SupramoleculeName: Complex structure of somatostatin receptor 4 (SSTR4) with Gi and J-2156
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Insecta environmental sample (insect)

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Macromolecule #1: Somatostatin receptor type 4

MacromoleculeName: Somatostatin receptor type 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.667375 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: DYKDDDDGAP SAPSTLPPGG EEGLGTAWPS AANASSAPAE AEEAVAGPGD ARAAGMVAIQ CIYALVCLVG LVGNALVIFV ILRYAKMKT ATNIYLLNLA VADELFMLSV PFVASSAALR HWPFGSVLCR AVLSVDGLNM FTSVFCLTVL SVDRYVAVVH P LRAATYRR ...String:
DYKDDDDGAP SAPSTLPPGG EEGLGTAWPS AANASSAPAE AEEAVAGPGD ARAAGMVAIQ CIYALVCLVG LVGNALVIFV ILRYAKMKT ATNIYLLNLA VADELFMLSV PFVASSAALR HWPFGSVLCR AVLSVDGLNM FTSVFCLTVL SVDRYVAVVH P LRAATYRR PSVAKLINLG VWLASLLVTL PIAIFADTRP ARGGQAVACN LQWPHPAWSA VFVVYTFLLG FLLPVLAIGL CY LLIVGKM RAVALRAGWQ QRRRSEKKIT RLVLMFVVVF VLCWMPFYVV QLLNLFVTSL DATVNHVSLI LSYANSCANP ILY GFLSDN FRRFFQRVLC LEFLEVLFQG PWSHPQFEKG GGSGGGSGGS AWSHPQFEK

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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: 40.447141 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKCTIV KQMKIIHEAG 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

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Macromolecule #3: single chain variable fragment of antibody

MacromoleculeName: single chain variable fragment of antibody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 31.549107 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: MKTIIALSYI FCLVFADYKD DDDGAPSEPD VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG S GGGGSDIV ...String:
MKTIIALSYI FCLVFADYKD DDDGAPSEPD VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG S GGGGSDIV MTQATSSVPV TPGESVSISC RSSKSLLHSN GNTYLYWFLQ RPGQSPQLLI YRMSNLASGV PDRFSGSGSG TA FTLTISR LEAEDVGVYY CMQHLEYPLT FGAGTKLELE FLEVLFQGPH HHHHH

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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

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Macromolecule #5: 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: 5 / 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

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Macromolecule #6: (2~{S})-2-[[(2~{S})-4-azanyl-2-[(4-methylnaphthalen-1-yl)sulfonyl...

MacromoleculeName: (2~{S})-2-[[(2~{S})-4-azanyl-2-[(4-methylnaphthalen-1-yl)sulfonylamino]butanoyl]amino]-3-phenyl-propanimidic acid
type: ligand / ID: 6 / Number of copies: 1 / Formula: I8B
Molecular weightTheoretical: 468.569 Da
Chemical component information

ChemComp-I8B:
(2~{S})-2-[[(2~{S})-4-azanyl-2-[(4-methylnaphthalen-1-yl)sulfonylamino]butanoyl]amino]-3-phenyl-propanimidic acid

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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: NICKEL/TITANIUM
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: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.3 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 600908

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