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- PDB-6pb0: Cryo-EM structure of Urocortin 1-bound Corticotropin-releasing fa... -

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Basic information

Entry
Database: PDB / ID: 6pb0
TitleCryo-EM structure of Urocortin 1-bound Corticotropin-releasing factor 1 receptor in complex with Gs protein and Nb35
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Corticotropin-releasing factor receptor 1
  • Nanobody 35Single-domain antibody
  • Urocortin
KeywordsSIGNALING PROTEIN / Corticotropin-releasing factor 1 receptor / urocortins1 / Gs protein / GPCR
Function / homology
Function and homology information


regulation of adenylate cyclase activity involved in G protein-coupled receptor signaling pathway / corticotropin-releasing hormone binding / histone deacetylase inhibitor activity / regulation of corticosterone secretion / corticotrophin-releasing factor receptor activity / corticotropin-releasing hormone receptor 2 binding / corticotropin secretion / general adaptation syndrome, behavioral process / positive regulation of corticotropin secretion / cellular response to corticotropin-releasing hormone stimulus ...regulation of adenylate cyclase activity involved in G protein-coupled receptor signaling pathway / corticotropin-releasing hormone binding / histone deacetylase inhibitor activity / regulation of corticosterone secretion / corticotrophin-releasing factor receptor activity / corticotropin-releasing hormone receptor 2 binding / corticotropin secretion / general adaptation syndrome, behavioral process / positive regulation of corticotropin secretion / cellular response to corticotropin-releasing hormone stimulus / positive regulation of behavioral fear response / parturition / negative regulation of hormone secretion / varicosity / negative regulation of voltage-gated calcium channel activity / response to auditory stimulus / drinking behavior / behavioral response to ethanol / negative regulation of appetite / corticotropin-releasing hormone receptor 1 binding / neuropeptide hormone activity / positive regulation of vascular permeability / fear response / G protein-coupled peptide receptor activity / negative regulation of cell size / Class B/2 (Secretin family receptors) / exploration behavior / response to pain / adrenal gland development / negative regulation of feeding behavior / startle response / positive regulation of calcium ion import / social behavior / PKA activation in glucagon signalling / associative learning / hair follicle placode formation / intracellular transport / Adenylate cyclase inhibitory pathway / D1 dopamine receptor binding / developmental growth / positive regulation of protein localization to cell cortex / neuropeptide signaling pathway / positive regulation of collagen biosynthetic process / regulation of cAMP-mediated signaling / Synthesis, secretion, and deacylation of Ghrelin / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / axon terminus / aerobic respiration / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of mitotic spindle organization / cellular response to forskolin / response to glucocorticoid / regulation of synaptic transmission, glutamatergic / positive regulation of cardiac muscle contraction / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / positive regulation of translation / trans-Golgi network membrane / positive regulation of DNA replication / Regulation of insulin secretion / G protein-coupled receptor binding / female pregnancy / sensory perception of sound / G-protein beta/gamma-subunit complex binding / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / bone development / 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / Glucagon-type ligand receptors / cognition / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production
Similarity search - Function
GPCR, family 2, corticotropin releasing factor receptor, type 1 / 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 1 / 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. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Few Secondary Structures / Irregular / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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 / Corticotropin-releasing factor receptor 1 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 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 1.1Feb 19, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

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Assembly

Deposited unit
R: Corticotropin-releasing factor receptor 1
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)156,95918
Polymers153,2306
Non-polymers3,72812
Water0
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 RUN

#1: Protein Corticotropin-releasing factor receptor 1 / CRFR-1 / Corticotropin-releasing hormone receptor 1 / CRH-R1


Mass: 43509.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRHR1, CRFR, CRFR1, CRHR
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P34998
#2: Protein/peptide Urocortin /


Mass: 4703.277 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: UCN / Production host: synthetic construct (others) / References: UniProt: P55089
#6: Antibody Nanobody 35 / Single-domain antibody


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, 12 molecules

#7: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical
ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C16H32O2

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Details

Has ligand of interestN

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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: Urocortin1-bound CRF1R in complex Gs and Nb35 / 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 FIELDBright-field microscopy
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
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 97386 / Symmetry type: POINT

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