+Open data
-Basic information
Entry | Database: PDB / ID: 8zbe | ||||||
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Title | cryo-EM structure of the octreotide-bound SSTR5-Gi complex | ||||||
Components |
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Keywords | MEMBRANE PROTEIN/IMMUNE SYSTEM / SSTR5 / octreoitde / structural protein / 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 / neuropeptide binding ...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 / neuropeptide binding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / : / beta2-adrenergic receptor activity / positive regulation of mini excitatory postsynaptic potential / positive regulation of cAMP-dependent protein kinase activity / Thrombin signalling through proteinase activated receptors (PARs) / cellular response to glucocorticoid stimulus / G alpha (i) signalling events / norepinephrine binding / alkylglycerophosphoethanolamine phosphodiesterase activity / Adrenoceptors / heat generation / positive regulation of AMPA receptor activity / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / photoreceptor outer segment membrane / response to psychosocial stress / negative regulation of multicellular organism growth / spectrin binding / adrenergic receptor signaling pathway / endosome to lysosome transport / diet induced thermogenesis / neuronal dense core vesicle / positive regulation of cytokinesis / positive regulation of protein kinase A signaling / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase binding / smooth muscle contraction / photoreceptor outer segment / potassium channel regulator activity / Adenylate cyclase inhibitory pathway / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / positive regulation of bone mineralization / bone resorption / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / brown fat cell differentiation / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / regulation of mitotic spindle organization / cellular response to forskolin / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / photoreceptor inner segment / response to cold / Peptide ligand-binding receptors / receptor-mediated endocytosis / Regulation of insulin secretion / G protein-coupled receptor binding / clathrin-coated endocytic vesicle membrane / G-protein beta/gamma-subunit complex binding / positive regulation of protein serine/threonine kinase activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / cellular response to amyloid-beta / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / Cargo recognition for clathrin-mediated endocytosis / GTPase binding / Clathrin-mediated endocytosis / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / amyloid-beta binding / cell cortex / midbody / positive regulation of cytosolic calcium ion concentration Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Oplophorus gracilirostris (crustacean) Rattus norvegicus (Norway rat) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.24 Å | ||||||
Authors | Li, Y.G. / Meng, X.Y. / Yang, X.R. / Ling, S.L. / Shi, P. / Tian, C.L. / Yang, F. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8zbe.cif.gz | 224.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8zbe.ent.gz | 159.8 KB | Display | PDB format |
PDBx/mmJSON format | 8zbe.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8zbe_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 8zbe_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 8zbe_validation.xml.gz | 38.8 KB | Display | |
Data in CIF | 8zbe_validation.cif.gz | 58.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zb/8zbe ftp://data.pdbj.org/pub/pdb/validation_reports/zb/8zbe | HTTPS FTP |
-Related structure data
Related structure data | 39901MC 8zcjC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BDC
#2: 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 |
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#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A9X9ZA26 |
#6: Protein | 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 |
-Protein / Antibody / Protein/peptide , 3 types, 3 molecules AEP
#1: Protein | 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 |
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#4: Antibody | Mass: 32708.473 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/peptide | Mass: 1036.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: octreotide-bound SSTR5-Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT | ||||||||||||||||||||
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Source (natural) |
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Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) | ||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN |
Electron lens | Mode: DIFFRACTION / Nominal defocus max: 2000 nm / Nominal defocus min: 1400 nm |
Image recording | Electron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
EM software | Name: PHENIX / Version: 1.20.1_4487: / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 452725 / Symmetry type: POINT | ||||||||||||||||||||||||
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