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- PDB-8zcj: Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex -

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Basic information

Entry
Database: PDB / ID: 8zcj
TitleCryo-EM structure of the pasireotide-bound SSTR5-Gi complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • 004-DTR-LYS-TYR-PHA-HYP
  • Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein)
  • ScFv16
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / pasireotide / SSTR5 / Cryo-EM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


somatostatin receptor activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels ...somatostatin receptor activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / neuropeptide binding / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of mini excitatory postsynaptic potential / beta2-adrenergic receptor activity / AMPA selective glutamate receptor signaling pathway / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / norepinephrine binding / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / heat generation / Adrenoceptors / activation of transmembrane receptor protein tyrosine kinase activity / G alpha (i) signalling events / negative regulation of smooth muscle contraction / 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 / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / cellular response to glucocorticoid stimulus / positive regulation of lipophagy / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / negative regulation of G protein-coupled receptor signaling pathway / negative regulation of multicellular organism growth / photoreceptor outer segment membrane / G alpha (q) signalling events / G alpha (i) signalling events / spectrin binding / adrenergic receptor signaling pathway / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / response to psychosocial stress / endosome to lysosome transport / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / diet induced thermogenesis / neuronal dense core vesicle / positive regulation of cytokinesis / alkylglycerophosphoethanolamine phosphodiesterase activity / positive regulation of cAMP/PKA signal transduction / adenylate cyclase binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / smooth muscle contraction / photoreceptor outer segment / neuropeptide signaling pathway / bone resorption / positive regulation of bone mineralization / potassium channel regulator activity / brown fat cell differentiation / intercellular bridge / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / regulation of sodium ion transport / adenylate cyclase-activating adrenergic receptor signaling pathway / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / photoreceptor inner segment / cardiac muscle cell apoptotic process / cellular response to forskolin / regulation of insulin secretion / receptor-mediated endocytosis / regulation of mitotic spindle organization / response to cold / Peptide ligand-binding receptors
Similarity search - Function
Somatostatin receptor 5 / Somatostatin receptor family / Beta 2 adrenoceptor / Adrenoceptor 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. ...Somatostatin receptor 5 / Somatostatin receptor family / Beta 2 adrenoceptor / Adrenoceptor 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. / 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
Beta-2 adrenergic receptor / Somatostatin receptor type 5 / 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)
Rattus norvegicus (Norway rat)
Bos taurus (domestic cattle)
Oplophorus gracilirostris (crustacean)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsLi, Y.G. / Meng, X.Y. / Yang, X.R. / Ling, S.L. / Shi, P. / Tian, C.L. / Yang, F.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: Acta Pharmacol Sin / Year: 2024
Title: Structural insights into somatostatin receptor 5 bound with cyclic peptides.
Authors: Ying-Ge Li / Xian-Yu Meng / Xiru Yang / Sheng-Long Ling / Pan Shi / Chang-Lin Tian / Fan Yang /
Abstract: Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides ...Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 Å and 3.24 Å, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/Trp of pasireotide and SSTR5. Moreover, we find that the Q, N, F and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.
History
DepositionApr 29, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: citation / em_admin ...citation / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(i) subunit alpha-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: ScFv16
G: Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein)
A: 004-DTR-LYS-TYR-PHA-HYP


Theoretical massNumber of molelcules
Total (without water)184,9766
Polymers184,9766
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40445.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 41055.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Antibody / Protein / Protein/peptide , 3 types, 3 molecules EGA

#4: Antibody ScFv16


Mass: 32724.473 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein) / Beta-2 adrenoreceptor / Beta-2 adrenoceptor / SS-5-R / SS5-R / SS5R / SST5


Mass: 62015.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Oplophorus gracilirostris (crustacean)
Gene: ADRB2, ADRB2R, B2AR, SSTR5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07550, UniProt: P35346
#6: Protein/peptide 004-DTR-LYS-TYR-PHA-HYP


Mass: 874.016 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: pasireotide-SSTR5-Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Bos taurus (domestic cattle)9913
41Rattus norvegicus (Norway rat)10116
51Oplophorus gracilirostris (crustacean)727944
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 2000 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1227503 / Symmetry type: POINT
RefinementCross valid method: NONE

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