+Open data
-Basic information
Entry | Database: PDB / ID: 8e3z | ||||||||||||||||||
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Title | Cryo-EM structure of the VPAC1R-VIP-Gs complex | ||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / drug discovery / G protein coupled receptor / signalling | ||||||||||||||||||
Function / homology | Function and homology information epinephrine secretion / positive regulation of epinephrine secretion / prolactin secretion / body fluid secretion / vasoactive intestinal polypeptide receptor activity / positive regulation of penile erection / neuropeptide hormone activity / mRNA stabilization / G protein-coupled peptide receptor activity / peptide hormone receptor binding ...epinephrine secretion / positive regulation of epinephrine secretion / prolactin secretion / body fluid secretion / vasoactive intestinal polypeptide receptor activity / positive regulation of penile erection / neuropeptide hormone activity / mRNA stabilization / G protein-coupled peptide receptor activity / peptide hormone receptor binding / peptide hormone binding / PKA activation in glucagon signalling / negative regulation of potassium ion transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hair follicle placode formation / developmental growth / intracellular transport / D1 dopamine receptor binding / positive regulation of cAMP-mediated signaling / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of endothelial cell proliferation / activation of adenylate cyclase activity / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of smooth muscle cell proliferation / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / cognition / photoreceptor disc membrane / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of GTPase activity / 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 / positive regulation of protein catabolic process / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / regulation of protein localization / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / learning or memory / cell surface receptor signaling pathway / receptor complex / neuron projection / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / positive regulation of cell population proliferation / protein-containing complex binding / GTP binding / negative regulation of apoptotic process / signal transduction Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) Lama glama (llama) | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | ||||||||||||||||||
Authors | Piper, S.J. / Danev, R. / Sexton, P. / Wootten, D. | ||||||||||||||||||
Funding support | Australia, United Kingdom, Japan, 5items
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Citation | Journal: Nat Commun / Year: 2022 Title: Understanding VPAC receptor family peptide binding and selectivity. Authors: Sarah J Piper / Giuseppe Deganutti / Jessica Lu / Peishen Zhao / Yi-Lynn Liang / Yao Lu / Madeleine M Fletcher / Mohammed Akhter Hossain / Arthur Christopoulos / Christopher A Reynolds / ...Authors: Sarah J Piper / Giuseppe Deganutti / Jessica Lu / Peishen Zhao / Yi-Lynn Liang / Yao Lu / Madeleine M Fletcher / Mohammed Akhter Hossain / Arthur Christopoulos / Christopher A Reynolds / Radostin Danev / Patrick M Sexton / Denise Wootten / Abstract: The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a ...The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists. | ||||||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8e3z.cif.gz | 217.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8e3z.ent.gz | 165.9 KB | Display | PDB format |
PDBx/mmJSON format | 8e3z.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/e3/8e3z ftp://data.pdbj.org/pub/pdb/validation_reports/e3/8e3z | HTTPS FTP |
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-Related structure data
Related structure data | 27874MC 8e3xC 8e3yC 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 ABG
#1: Protein | Mass: 45699.434 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63092 |
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#2: Protein | Mass: 38534.062 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873 |
#3: 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768 |
-Vasoactive intestinal ... , 2 types, 2 molecules PR
#5: Protein/peptide | Mass: 3332.831 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01282 |
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#6: Protein | Mass: 52620.684 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: VIPR1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P32241 |
-Antibody / Non-polymers , 2 types, 6 molecules N
#4: Antibody | Mass: 15140.742 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli) |
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#7: Water | ChemComp-HOH / |
-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 |
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||||||||
Specimen | Conc.: 3.9 mg/ml / 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: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 47 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) Details: Movies were collected in two sets with 64.9 e-/A2 dose (1134 movies) and 47 e-/A2 dose (4329 movies) and combined in the data processing. |
-Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 375164 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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