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- PDB-7ys6: Cryo-EM structure of the Serotonin 6 (5-HT6) receptor-DNGs-scFv16... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7ys6 | ||||||
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Title | Cryo-EM structure of the Serotonin 6 (5-HT6) receptor-DNGs-scFv16 complex | ||||||
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![]() | MEMBRANE PROTEIN / GPCR / serotonin receptor / 5-HT6R / cryo-EM / constitutive activity | ||||||
Function / homology | ![]() histamine receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / cerebral cortex cell migration / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of TOR signaling / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta ...histamine receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / cerebral cortex cell migration / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of TOR signaling / 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 / 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 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / cilium / 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 / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / dendrite / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | ||||||
![]() | Zhao, Q.Y. / Wang, Y.F. / He, L. / Wang, S. / Cong, Y. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural insights into constitutive activity of 5-HT receptor. Authors: Licong He / Qiaoyu Zhao / Jianzhong Qi / Yifan Wang / Wenyu Han / Zhangcheng Chen / Yao Cong / Sheng Wang / ![]() Abstract: While most therapeutic research on G-protein-coupled receptors (GPCRs) focuses on receptor activation by (endogenous) agonists, significant therapeutic potential exists through agonist-independent ...While most therapeutic research on G-protein-coupled receptors (GPCRs) focuses on receptor activation by (endogenous) agonists, significant therapeutic potential exists through agonist-independent intrinsic constitutive activity that can occur in various physiological and pathophysiological settings. For example, inhibiting the constitutive activity of 5-HTR-a receptor that is found almost exclusively in the brain and mediates excitatory neurotransmission-has demonstrated a therapeutic effect on cognitive/memory impairment associated with several neuropsychiatric disorders. However, the structural basis of such constitutive activity remains unclear. Here, we present a cryo-EM structure of serotonin-bound human 5-HTR-Gs heterotrimer at 3.0-Å resolution. Detailed analyses of the structure complemented by comprehensive interrogation of signaling illuminate key structural determinants essential for constitutive 5-HTR activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gαs for 5-HTR that can reduce its constitutive activity. Given the importance of 5-HTR for a large number of neuropsychiatric disorders, insights derived from these studies will accelerate the design of more effective medications, and shed light on the molecular basis of constitutive activity. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 232.9 KB | Display | ![]() |
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PDB format | ![]() | 179.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 41.1 KB | Display | |
Data in CIF | ![]() | 60.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 34073MC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 33201.918 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#5: Protein | Mass: 43385.246 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD
#2: Protein | Mass: 39385.957 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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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.) ![]() ![]() |
-Antibody / Non-polymers , 2 types, 2 molecules E![](data/chem/img/SRO.gif)
![](data/chem/img/SRO.gif)
#4: Antibody | Mass: 28636.793 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#6: Chemical | ChemComp-SRO / |
-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 |
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Sample preparation
Component | Name: Serotonin 6 (5-HT6) receptor-DNGs-scFv16 complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 50.2 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.20rc1_4392: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 388504 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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