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- EMDB-26103: Cryo-EM structure of corticotropin releasing factor receptor 2 bo... -

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Entry
Database: EMDB / ID: EMD-26103
TitleCryo-EM structure of corticotropin releasing factor receptor 2 bound to Urocortin 1 and coupled with heterotrimeric G11 protein
Map data
Sample
  • Complex: Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1) and coupled with G11 proteins
    • Protein or peptide: Corticotropin-releasing factor receptor 2
    • Protein or peptide: Urocortin
    • Protein or peptide: Guanine nucleotide-binding protein subunit alpha-11
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: G protein gamma subunit
    • Protein or peptide: scFV16
KeywordsGPCR / corticotropin releasing factor receptor 2 / Urocortin 1 / G11 protein / SIGNALING PROTEIN
Function / homology
Function and homology information


histone deacetylase inhibitor activity / corticotropin-releasing hormone receptor activity / regulation of melanocyte differentiation / corticotrophin-releasing factor receptor activity / corticotropin-releasing hormone receptor 2 binding / positive regulation of corticotropin secretion / positive regulation of behavioral fear response / varicosity / : / phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway ...histone deacetylase inhibitor activity / corticotropin-releasing hormone receptor activity / regulation of melanocyte differentiation / corticotrophin-releasing factor receptor activity / corticotropin-releasing hormone receptor 2 binding / positive regulation of corticotropin secretion / positive regulation of behavioral fear response / varicosity / : / phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / negative regulation of hormone secretion / Acetylcholine regulates insulin secretion / endothelin receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway / developmental pigmentation / response to auditory stimulus / drinking behavior / PLC beta mediated events / cranial skeletal system development / cellular response to pH / negative regulation of appetite / entrainment of circadian clock / corticotropin-releasing hormone receptor 1 binding / neuropeptide hormone activity / negative regulation of cell size / 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 / positive regulation of vascular permeability / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / Class B/2 (Secretin family receptors) / 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 / spectrin binding / negative regulation of feeding behavior / positive regulation of calcium ion import / startle response / ligand-gated ion channel signaling pathway / alkylglycerophosphoethanolamine phosphodiesterase activity / social behavior / associative learning / peptide hormone binding / positive regulation of cAMP/PKA signal transduction / action potential / phototransduction, visible light / positive regulation of collagen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / photoreceptor outer segment / neuropeptide signaling pathway / response to glucocorticoid / regulation of synaptic transmission, glutamatergic / enzyme regulator activity / negative regulation of blood pressure / axon terminus / photoreceptor inner segment / cardiac muscle cell apoptotic process / positive regulation of cardiac muscle contraction / aerobic respiration / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of translation / positive regulation of DNA replication / skeletal system development / female pregnancy / sensory perception of sound / G protein-coupled receptor binding / positive regulation of insulin secretion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / regulation of blood pressure / positive regulation of interleukin-6 production / G-protein beta/gamma-subunit complex binding / long-term synaptic potentiation / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / neuron projection development / vasodilation / ADP signalling through P2Y purinoceptor 1 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / heterotrimeric G-protein complex / sensory perception of taste / response to estradiol / signaling receptor complex adaptor activity
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 alpha subunit, group Q / 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 alpha subunit, group Q / 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. / 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 / 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. / WD domain, G-beta repeat / 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
Similarity search - Domain/homology
Guanine nucleotide-binding protein subunit alpha-11 / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsZhao L-H / Lin J / Mao C / Zhou XE / Ji S / Shen D / Xiao P / Melcher K / Zhang Y / Yu X / Xu HE
Funding support China, United States, 5 items
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, 2022-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26103.png

Downloads & links

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Map

FileDownload / File: emd_26103.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 224 pix.
= 234.08 Å		1.05 Å/pix.
x 224 pix.
= 234.08 Å		1.05 Å/pix.
x 224 pix.
= 234.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.013
Minimum - Maximum-0.038500823 - 0.080725834
Average (Standard dev.)-0.000060674607 (±0.0032049895)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 234.07999 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocor...

EntireName: Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1) and coupled with G11 proteins
Components
  • Complex: Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1) and coupled with G11 proteins
    • Protein or peptide: Corticotropin-releasing factor receptor 2
    • Protein or peptide: Urocortin
    • Protein or peptide: Guanine nucleotide-binding protein subunit alpha-11
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: G protein gamma subunit
    • Protein or peptide: scFV16

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Supramolecule #1: Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocor...

SupramoleculeName: Corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1) and coupled with G11 proteins
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Corticotropin-releasing factor receptor 2

MacromoleculeName: Corticotropin-releasing factor receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.716246 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DAALLHSLLE ANCSLALAEE LLLDGWGPPL DPEGPYSYCN TTLDQIGTCW PRSAAGALVE RPCPEYFNGV KYNTTRNAYR ECLENGTWA SKINYSQCEP ILDDKQRKYD LHYRIALVVN YLGHCVSVAA LVAAFLLFLA LRSIRCLRNV IHWNLITTFI L RNVMWFLL ...String:
DAALLHSLLE ANCSLALAEE LLLDGWGPPL DPEGPYSYCN TTLDQIGTCW PRSAAGALVE RPCPEYFNGV KYNTTRNAYR ECLENGTWA SKINYSQCEP ILDDKQRKYD LHYRIALVVN YLGHCVSVAA LVAAFLLFLA LRSIRCLRNV IHWNLITTFI L RNVMWFLL QLVDHEVHES NEVWCRCITT IFNYFVVTNF FWMFVEGCYL HTAIVMTYST ERLRKCLFLF IGWCIPFPII VA WAIGKLY YENEQCWFGK EPGDLVDYIY QGPIILVLLI NFVFLFNIVR ILMTKLRAST TSETIQYRKA VKATLVLLPL LGI TYMLFF VNPGEDDLSQ IMFIYFNSFL QSFQGFFVSV FYCFFNGEVR SAVRKRWHRW QDHHSLRVPM AGSSGGGGSG GGGS SGVFT LEDFVGDWEQ TAAYNLDQVL EQGGVSSLLQ NLAVSVTPIQ RIVRSGENAL KIDIHVIIPY EGLSADQMAQ IEEVF KVVY PVDDHHFKVI LPYGTLVIDG VTPNMLNYFG RPYEGIAVFD GKKITVTGTL WNGNKIIDER LITPDGSMLF RVTINS

UniProtKB: Corticotropin-releasing factor receptor 2

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Macromolecule #2: Urocortin

MacromoleculeName: Urocortin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.703277 KDa
SequenceString:
DNPSLSIDLT FHLLRTLLEL ARTQSQRERA EQNRIIFDSV

UniProtKB: Urocortin

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Macromolecule #3: Guanine nucleotide-binding protein subunit alpha-11

MacromoleculeName: Guanine nucleotide-binding protein subunit alpha-11 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.415348 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLRRDKRDA RRELKLLLLG TGESGKSTFI KQMRIIHGAG YSEEDKRGFT KLVYQNIFTA MQAMIRAME TLKILYKYEQ NKANALLIRE VDVEKVTTFE HQYVSAIKTL WEDPGIQECY DRRREYQLSD SAKYYLTDVD R IATLGYLP ...String:
MGCTLSAEDK AAVERSKMIE KQLRRDKRDA RRELKLLLLG TGESGKSTFI KQMRIIHGAG YSEEDKRGFT KLVYQNIFTA MQAMIRAME TLKILYKYEQ NKANALLIRE VDVEKVTTFE HQYVSAIKTL WEDPGIQECY DRRREYQLSD SAKYYLTDVD R IATLGYLP TQQDVLRVRV PTTGIIEYPF DLENIIFRMV DVGAQRSERR KWIHCFENVT SIMFLVALSE YDQVLVESDN EN RMEESKA LFRTIITYPW FQNSSVILFL NKKDLLEDKI LYSHLVDYFP EFDGPQRDAQ AAREFILKMF VDLNPDSDKI IYS HFTCST DTENIRFVFA AVKDTILQLN LKEYNLV

UniProtKB: Guanine nucleotide-binding protein subunit alpha-11

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 43.70675 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHSSG LVPRGSHMAS HHHHHHHHHH GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN L KTREGNVR ...String:
MHHHHHHSSG LVPRGSHMAS HHHHHHHHHH GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN L KTREGNVR VSRELAGHTG YLSCCRFLDD NQIVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DA SAKLWDV REGMCRQTFT GHESDINAIC FFPNGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLL AGYDDF NCNVWDALKA DRAGVLAGHD NRVSCLGVTD DGMAVATGSW DSFLKIWNGS SGGGGSGGGG SSGVSGWRLF KKIS

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #5: G protein gamma subunit

MacromoleculeName: G protein gamma subunit / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #6: scFV16

MacromoleculeName: scFV16 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6pb1

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 155167
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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