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- PDB-7ts0: Cryo-EM structure of corticotropin releasing factor receptor 2 bo... -

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Basic information

Entry
Database: PDB / ID: 7ts0
TitleCryo-EM structure of corticotropin releasing factor receptor 2 bound to Urocortin 1 and coupled with heterotrimeric Go protein
Components
  • Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Human corticotropin releasing factor receptor 2
  • Dominant negative Go alpha subunit
  • G protein gamma subunit
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Urocortin
  • scFV16
KeywordsSIGNALING PROTEIN / GPCR / corticotropin releasing factor receptor 2 / Urocortin 1 / Go protein
Function / homology
Function and homology information


histone deacetylase inhibitor activity / corticotropin-releasing hormone receptor activity / corticotrophin-releasing factor receptor activity / corticotropin-releasing hormone receptor 2 binding / positive regulation of corticotropin secretion / positive regulation of behavioral fear response / varicosity / negative regulation of hormone secretion / drinking behavior / response to auditory stimulus ...histone deacetylase inhibitor activity / corticotropin-releasing hormone receptor activity / corticotrophin-releasing factor receptor activity / corticotropin-releasing hormone receptor 2 binding / positive regulation of corticotropin secretion / positive regulation of behavioral fear response / varicosity / negative regulation of hormone secretion / drinking behavior / response to auditory stimulus / negative regulation of appetite / neuropeptide hormone activity / positive regulation of vascular permeability / corticotropin-releasing hormone receptor 1 binding / 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 / negative regulation of cell size / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Class B/2 (Secretin family receptors) / Vasopressin regulates renal water homeostasis via Aquaporins / G protein-coupled peptide receptor activity / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / photoreceptor outer segment membrane / response to pain / negative regulation of feeding behavior / spectrin binding / positive regulation of calcium ion import / startle response / alkylglycerophosphoethanolamine phosphodiesterase activity / positive regulation of cAMP/PKA signal transduction / peptide hormone binding / positive regulation of collagen biosynthetic process / associative learning / social behavior / Synthesis, secretion, and deacylation of Ghrelin / photoreceptor outer segment / neuropeptide signaling pathway / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / cardiac muscle cell apoptotic process / photoreceptor inner segment / axon terminus / positive regulation of cardiac muscle contraction / response to glucocorticoid / aerobic respiration / positive regulation of translation / positive regulation of DNA replication / sensory perception of sound / female pregnancy / positive regulation of interleukin-6 production / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / vasodilation / long-term synaptic potentiation / neuron projection development / response to estradiol / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / cell body / GTPase binding / positive regulation of cell growth / response to oxidative stress / perikaryon / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to hypoxia / negative regulation of neuron apoptotic process / cell surface receptor signaling pathway / cell population proliferation / G protein-coupled receptor signaling pathway / negative regulation of gene expression / GTPase activity / synapse / dendrite / protein-containing complex binding / positive regulation of transcription by RNA polymerase II / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
GPCR, family 2, corticotropin releasing factor receptor, type 2 / Urocortin/corticotropin-releasing factor / Corticotropin-releasing factor conserved site / Corticotropin-releasing factor family signature. / corticotropin-releasing factor / Corticotropin-releasing factor / GPCR, family 2, corticotropin releasing factor receptor / Corticotropin-releasing factor family / G-protein coupled receptors family 2 signature 1. / : ...GPCR, family 2, corticotropin releasing factor receptor, type 2 / Urocortin/corticotropin-releasing factor / Corticotropin-releasing factor conserved site / Corticotropin-releasing factor family signature. / corticotropin-releasing factor / Corticotropin-releasing factor / GPCR, family 2, corticotropin releasing factor receptor / Corticotropin-releasing factor family / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Urocortin / Corticotropin-releasing factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhao, L.-H. / Lin, J. / Mao, C. / Zhou, X.E. / Ji, S. / Shen, D. / Xiao, P. / Melcher, K. / Zhang, Y. / Yu, X. / Xu, H.E.
Funding support China, United States, 5items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071203 China
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM127710 United States
National Natural Science Foundation of China (NSFC)31971195 China
National Natural Science Foundation of China (NSFC)81922071 China
National Natural Science Foundation of China (NSFC)32100959 China
CitationJournal: Nat Commun / Year: 2022
Title: Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor.
Authors: Li-Hua Zhao / Jingyu Lin / Su-Yu Ji / X Edward Zhou / Chunyou Mao / Dan-Dan Shen / Xinheng He / Peng Xiao / Jinpeng Sun / Karsten Melcher / Yan Zhang / Xiao Yu / H Eric Xu /
Abstract: The ability to couple with multiple G protein subtypes, such as G, G, or G, by a given G protein-coupled receptor (GPCR) is critical for many physiological processes. Over the past few years, the ...The ability to couple with multiple G protein subtypes, such as G, G, or G, by a given G protein-coupled receptor (GPCR) is critical for many physiological processes. Over the past few years, the cryo-EM structures for all 15 members of the medically important class B GPCRs, all in complex with G protein, have been determined. However, no structure of class B GPCRs with G has been solved to date, limiting our understanding of the precise mechanisms of G protein coupling selectivity. Here we report the structures of corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1), coupled with different classes of heterotrimeric G proteins, G and G. We compare these structures with the structure of CRF2R in complex with G to uncover the structural differences that determine the selective coupling of G protein subtypes by CRF2R. These results provide important insights into the structural basis for the ability of CRF2R to couple with multiple G protein subtypes.
History
DepositionJan 31, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Nov 9, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 16, 2022Group: Database references / Category: citation / citation_author
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Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3May 14, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 14, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
P: Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Human corticotropin releasing factor receptor 2
U: Urocortin
A: Dominant negative Go alpha subunit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: G protein gamma subunit
H: scFV16


Theoretical massNumber of molelcules
Total (without water)186,2976
Polymers186,2976
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 4 molecules PABG

#1: Protein Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Corticotropin-releasing factor receptor 2,Human corticotropin releasing factor receptor 2 / CRF-R-2 / CRF-R2 / CRFR-2 / Corticotropin-releasing hormone receptor 2 / CRH-R-2 / CRH-R2


Mass: 63716.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRHR2, CRF2R, CRH2R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13324
#3: Protein Dominant negative Go alpha subunit


Mass: 40032.488 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)
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 43706.750 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
#5: Protein G protein gamma subunit


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)

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Protein/peptide / Antibody , 2 types, 2 molecules UH

#2: Protein/peptide Urocortin


Mass: 4703.277 Da / Num. of mol.: 1 / Fragment: UNP residues 83-122 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P55089
#6: Antibody scFV16


Mass: 26277.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1) and coupled with G11 proteins
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 4000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 171435 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039851
ELECTRON MICROSCOPYf_angle_d0.80113350
ELECTRON MICROSCOPYf_dihedral_angle_d11.2976172
ELECTRON MICROSCOPYf_chiral_restr0.0531499
ELECTRON MICROSCOPYf_plane_restr0.0061665

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