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Yorodumi- PDB-7xms: CryoEM structure of somatostatin receptor 4 (SSTR4) in complex wi... -
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-Basic information
Entry | Database: PDB / ID: 7xms | |||||||||||||||||||||||||||
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Title | CryoEM structure of somatostatin receptor 4 (SSTR4) in complex with Gi1 and its endogeneous ligand SST-14 | |||||||||||||||||||||||||||
Components |
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Keywords | SIGNALING PROTEIN / G protein-coupled receptor / somatostatin receptor 4 / cryo-EM / STRUCTURAL PROTEIN | |||||||||||||||||||||||||||
Function / homology | Function and homology information somatostatin signaling pathway / somatostatin receptor activity / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / MECP2 regulates transcription of neuronal ligands / hormone-mediated apoptotic signaling pathway / positive regulation of arachidonic acid secretion / neuropeptide binding / response to acidic pH / hyperosmotic response / cellular response to glucocorticoid stimulus ...somatostatin signaling pathway / somatostatin receptor activity / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / MECP2 regulates transcription of neuronal ligands / hormone-mediated apoptotic signaling pathway / positive regulation of arachidonic acid secretion / neuropeptide binding / response to acidic pH / hyperosmotic response / cellular response to glucocorticoid stimulus / response to steroid hormone / neuronal dense core vesicle / regulation of postsynaptic membrane neurotransmitter receptor levels / plasma membrane => GO:0005886 / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / GABA-ergic synapse / regulation of cAMP-mediated signaling / response to amino acid / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / forebrain development / regulation of mitotic spindle organization / cellular response to forskolin / regulation of cell migration / digestion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / response to nutrient / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / peptide binding / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / 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 / hormone activity / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / response to peptide hormone / 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 / G-protein beta-subunit binding / GDP binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / cell migration / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / cell-cell signaling / 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 / chemical synaptic transmission / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / neuron projection / response to xenobiotic stimulus / cell cycle / G protein-coupled receptor signaling pathway Similarity search - Function | |||||||||||||||||||||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | |||||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||||||||||||||||||||
Authors | Wenli, Z. / Shuo, H. / Na, Q. / Wenbo, Z. / Mengjie, L. / Dehua, Y. / Ming-Wei, W. / Wu, B. / Zhao, Q. | |||||||||||||||||||||||||||
Funding support | China, 8items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7xms.cif.gz | 208.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7xms.ent.gz | 156.8 KB | Display | PDB format |
PDBx/mmJSON format | 7xms.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/xm/7xms ftp://data.pdbj.org/pub/pdb/validation_reports/xm/7xms | HTTPS FTP |
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-Related structure data
Related structure data | 33303MC 7xmrC 7xmtC 7xn9C 7xnaC 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 ABC
#2: Protein | Mass: 40403.090 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Insecta environmental sample (insect) / References: UniProt: P63096 |
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#3: Protein | Mass: 38744.371 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Insecta environmental sample (insect) / References: UniProt: P62873 |
#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Insecta environmental sample (insect) / References: UniProt: P59768 |
-Protein / Antibody / Protein/peptide , 3 types, 3 molecules RSL
#1: Protein | Mass: 40667.375 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SSTR4 / Production host: Insecta environmental sample (insect) / References: UniProt: P31391 |
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#5: Antibody | Mass: 31549.107 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Insecta environmental sample (insect) |
#6: Protein/peptide | Mass: 1641.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P61278 |
-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: Complex structure of somatostatin receptor 4 (SSTR4) in complex with Gi and its endogeneous ligand SST-14 Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Insecta environmental sample (insect) |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: NICKEL/TITANIUM |
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: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2300 nm / Nominal defocus min: 1300 nm |
Image recording | Electron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 799646 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Refine LS restraints |
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