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- PDB-6pb1: Cryo-EM structure of Urocortin 1-bound Corticotropin-releasing fa... -

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Entry
Database: PDB / ID: 6pb1
TitleCryo-EM structure of Urocortin 1-bound Corticotropin-releasing factor 2 receptor in complex with Gs protein and Nb35
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Corticotropin-releasing factor receptor 2
  • Nanobody 35
  • Urocortin
KeywordsSIGNALING PROTEIN / Corticotropin-releasing factor 2 receptor / urocortins1 / Gs protein / GPCR
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 / negative regulation of cell size / Class B/2 (Secretin family receptors) / G protein-coupled peptide receptor activity / response to pain / negative regulation of feeding behavior / positive regulation of calcium ion import / startle response / positive regulation of cAMP/PKA signal transduction / peptide hormone binding / positive regulation of collagen biosynthetic process / associative learning / PKA activation in glucagon signalling / social behavior / Synthesis, secretion, and deacylation of Ghrelin / developmental growth / hair follicle placode formation / neuropeptide signaling pathway / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / regulation of synaptic transmission, glutamatergic / renal water homeostasis / activation of adenylate cyclase activity / adenylate cyclase inhibitor activity / Hedgehog 'off' state / positive regulation of protein localization to cell cortex / negative regulation of blood pressure / T cell migration / Adenylate cyclase inhibitory pathway / adenylate cyclase-activating adrenergic receptor signaling pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / axon terminus / positive regulation of cardiac muscle contraction / cellular response to glucagon stimulus / regulation of insulin secretion / cellular response to forskolin / response to glucocorticoid / regulation of mitotic spindle organization / aerobic respiration / positive regulation of translation / adenylate cyclase activator activity / positive regulation of DNA replication / trans-Golgi network membrane / Regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / positive regulation of cholesterol biosynthetic process / sensory perception of sound / female pregnancy / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of interleukin-6 production / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / platelet aggregation / G-protein beta/gamma-subunit complex binding / centriolar satellite / vasodilation / cognition / Olfactory Signaling Pathway / Activation of the phototransduction cascade / long-term synaptic potentiation / adenylate cyclase-activating 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-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / neuron projection development / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion
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 / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 ...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 / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / 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. / G-protein alpha subunit, group S / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / Few Secondary Structures / Irregular / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / WD domain, G-beta repeat / 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 / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
CHOLESTEROL / PALMITIC ACID / Urocortin / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Corticotropin-releasing factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsMa, S. / Shen, Q. / Zhao, L.-H. / Mao, C. / Zhou, X.E. / Shen, D.-D. / de Waal, P.W. / Bi, P. / Li, C. / Jiang, Y. ...Ma, S. / Shen, Q. / Zhao, L.-H. / Mao, C. / Zhou, X.E. / Shen, D.-D. / de Waal, P.W. / Bi, P. / Li, C. / Jiang, Y. / Wang, M.-W. / Sexton, P.M. / Wootten, D. / Melcher, K. / Zhang, Y. / Xu, H.E.
Funding support United States, China, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM127710 United States
National Natural Science Foundation of China (NSFC)31770796 China
CitationJournal: Mol Cell / Year: 2020
Title: Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors.
Authors: Shanshan Ma / Qingya Shen / Li-Hua Zhao / Chunyou Mao / X Edward Zhou / Dan-Dan Shen / Parker W de Waal / Peng Bi / Chuntao Li / Yi Jiang / Ming-Wei Wang / Patrick M Sexton / Denise Wootten ...Authors: Shanshan Ma / Qingya Shen / Li-Hua Zhao / Chunyou Mao / X Edward Zhou / Dan-Dan Shen / Parker W de Waal / Peng Bi / Chuntao Li / Yi Jiang / Ming-Wei Wang / Patrick M Sexton / Denise Wootten / Karsten Melcher / Yan Zhang / H Eric Xu /
Abstract: Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of ...Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.
History
DepositionJun 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Feb 12, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Jun 4, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 4, 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

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Assembly

Deposited unit
P: Corticotropin-releasing factor receptor 2
U: Urocortin
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody 35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,66615
Polymers154,8376
Non-polymers2,8299
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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#3: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein / Adenylate cyclase-inhibiting G alpha protein / ...Adenylate cyclase-stimulating G alpha protein / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein


Mass: 43897.789 Da / Num. of mol.: 1 / Mutation: A212G, S352A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP, GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092, UniProt: P63096
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein / Protein/peptide / Antibody , 3 types, 3 molecules PUN

#1: Protein Corticotropin-releasing factor receptor 2 / CRFR-2 / Corticotropin-releasing hormone receptor 2 / CRH-R2


Mass: 45116.375 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
#2: Protein/peptide Urocortin


Mass: 4703.277 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P55089
#6: Antibody Nanobody 35


Mass: 15343.019 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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Non-polymers , 2 types, 9 molecules

#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C16H32O2

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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: Urocortin 1-bound corticotropin-releasing factor 2 receptor in complex with Gs protein
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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
Image recordingElectron dose: 66 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 67569 / Symmetry type: POINT

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