+Open data
-Basic information
Entry | Database: PDB / ID: 8zcj | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex | ||||||
Components |
| ||||||
Keywords | MEMBRANE 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 / 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 / G alpha (i) signalling events / positive regulation of cAMP-dependent protein kinase activity / Thrombin signalling through proteinase activated receptors (PARs) / cellular response to glucocorticoid stimulus / 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 / norepinephrine binding / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / activation of transmembrane receptor protein tyrosine kinase activity / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / negative regulation of smooth muscle contraction / positive regulation of lipophagy / G alpha (q) signalling events / photoreceptor outer segment membrane / response to psychosocial stress / G alpha (i) signalling events / negative regulation of multicellular organism growth / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / adrenergic receptor signaling pathway / endosome to lysosome transport / diet induced thermogenesis / neuronal dense core vesicle / positive regulation of protein kinase A signaling / positive regulation of cytokinesis / 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 / D2 dopamine receptor binding / positive regulation of bone mineralization / 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 / bone resorption / cardiac muscle cell apoptotic process / activation of adenylate cyclase activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cold / photoreceptor inner segment / Peptide ligand-binding receptors / receptor-mediated endocytosis / Regulation of insulin secretion / G protein-coupled receptor binding / clathrin-coated endocytic vesicle membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Rattus norvegicus (Norway rat) Bos taurus (cattle) Oplophorus gracilirostris (crustacean) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å | ||||||
Authors | Li, Y.G. / Meng, X.Y. / Yang, X.R. / Ling, S.L. / Shi, P. / Tian, C.L. / Yang, F. | ||||||
Funding support | 1items
| ||||||
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 |
|
-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
---|
-Downloads & links
-Download
PDBx/mmCIF format | 8zcj.cif.gz | 232.7 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb8zcj.ent.gz | 166.2 KB | Display | PDB format |
PDBx/mmJSON format | 8zcj.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8zcj_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 8zcj_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 8zcj_validation.xml.gz | 39 KB | Display | |
Data in CIF | 8zcj_validation.cif.gz | 59 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zc/8zcj ftp://data.pdbj.org/pub/pdb/validation_reports/zc/8zcj | HTTPS FTP |
-Related structure data
Related structure data | 39931 39901 8zbeC M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD
#1: 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 | 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 | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212 |
-Antibody / Protein / Protein/peptide , 3 types, 3 molecules EGA
#4: Antibody | 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 | 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 | Mass: 874.016 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: pasireotide-SSTR5-Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Source (natural) |
| ||||||||||||||||||||
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 |
---|---|
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 |
---|---|
CTF correction | Type: NONE |
3D reconstruction | Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1227503 / Symmetry type: POINT |
Refinement | Cross valid method: NONE |