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- PDB-7f8w: Cryo-EM structure of the cholecystokinin receptor CCKBR in comple... -

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Basic information

Entry
Database: PDB / ID: 7f8w
TitleCryo-EM structure of the cholecystokinin receptor CCKBR in complex with gastrin-17 and Gq
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Gastrin-17
  • Gastrin/cholecystokinin type B receptor
  • scFv16
KeywordsSTRUCTURAL PROTEIN / G protein-coulped receptor / Cholecystokinin receptor CCKBR / Gastrin-17
Function / homology
Function and homology information


gastrin receptor activity / type B gastrin/cholecystokinin receptor binding / gland development / cholecystokinin receptor activity / cholecystokinin signaling pathway / gastric acid secretion / pH reduction / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events ...gastrin receptor activity / type B gastrin/cholecystokinin receptor binding / gland development / cholecystokinin receptor activity / cholecystokinin signaling pathway / gastric acid secretion / pH reduction / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / regulation of platelet activation / 1-phosphatidylinositol-3-kinase regulator activity / phototransduction, visible light / digestive tract development / Gastrin-CREB signalling pathway via PKC and MAPK / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / action potential / peptide hormone binding / photoreceptor outer segment / GTPase activator activity / Peptide ligand-binding receptors / G protein-coupled receptor binding / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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 / G-protein activation / 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 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / blood coagulation / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (q) signalling events / nuclear membrane / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / protein stabilization / G protein-coupled receptor signaling pathway / lysosomal membrane / intracellular membrane-bounded organelle / GTPase activity / positive regulation of cell population proliferation / synapse / protein-containing complex binding / GTP binding / Golgi apparatus / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Gastrin receptor / Cholecystokinin receptor / G-protein alpha subunit, group Q / 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 / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...Gastrin receptor / Cholecystokinin receptor / G-protein alpha subunit, group Q / 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 / 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 / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / 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. / WD domain, G-beta repeat / 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
Gastrin/cholecystokinin type B receptor / Guanine nucleotide-binding protein G(q) subunit alpha / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsZhang, X. / He, C. / Wang, M. / Zhou, Q. / Yang, D. / Zhu, Y. / Wu, B. / Zhao, Q.
Funding support China, 10items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)21704064 China
National Science Foundation (NSF, China)81773792 China
National Science Foundation (NSF, China)81973373 China
National Science Foundation (NSF, China)31800621 China
National Science Foundation (NSF, China)31770796 China
National Science Foundation (NSF, China)31971178 China
National Science Foundation (NSF, China)81872915 China
National Science Foundation (NSF, China)82073904 China
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)81525024 China
CitationJournal: Nat Chem Biol / Year: 2021
Title: Structures of the human cholecystokinin receptors bound to agonists and antagonists.
Authors: Xuefeng Zhang / Chenglin He / Mu Wang / Qingtong Zhou / Dehua Yang / Ya Zhu / Wenbo Feng / Hui Zhang / Antao Dai / Xiaojing Chu / Jia Wang / Zhenlin Yang / Yi Jiang / Ulrich Sensfuss / ...Authors: Xuefeng Zhang / Chenglin He / Mu Wang / Qingtong Zhou / Dehua Yang / Ya Zhu / Wenbo Feng / Hui Zhang / Antao Dai / Xiaojing Chu / Jia Wang / Zhenlin Yang / Yi Jiang / Ulrich Sensfuss / Qiuxiang Tan / Shuo Han / Steffen Reedtz-Runge / H Eric Xu / Suwen Zhao / Ming-Wei Wang / Beili Wu / Qiang Zhao /
Abstract: Cholecystokinin receptors, CCKR and CCKR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal ...Cholecystokinin receptors, CCKR and CCKR, are important neurointestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here, we report three crystal structures of the human CCKR in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCKR-gastrin in complex with G and G, respectively. These structures reveal the recognition pattern of different ligand types and the molecular basis of peptide selectivity in the cholecystokinin receptor family. By comparing receptor structures in different conformational states, a stepwise activation process of cholecystokinin receptors is proposed. Combined with pharmacological data, our results provide atomic details for differential ligand recognition and receptor activation mechanisms. These insights will facilitate the discovery of potential therapeutics targeting cholecystokinin receptors.
History
DepositionJul 2, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(q) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
D: scFv16
E: Gastrin-17
R: Gastrin/cholecystokinin type B receptor


Theoretical massNumber of molelcules
Total (without water)169,2036
Polymers169,2036
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10790 Å2
ΔGint-53 kcal/mol
Surface area47630 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

#1: Protein Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein alpha-q


Mass: 41353.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAQ, GAQ / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P50148
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P62873
#3: 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: Baculovirus expression vector pFastBac1-HM / References: UniProt: P59768

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

#4: Antibody scFv16


Mass: 28621.141 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Baculovirus expression vector pFastBac1-HM
#5: Protein/peptide Gastrin-17


Mass: 2098.203 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#6: Protein Gastrin/cholecystokinin type B receptor / CCK-B receptor / CCK-BR / Cholecystokinin-2 receptor / CCK2-R


Mass: 50524.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCKBR / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P32239

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Details

Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cholecystokinin recetor CCKBR in complex with gastrin-17 and GqCOMPLEXall0RECOMBINANT
2Guanine nucleotide-binding protein G subunitsCOMPLEX#1-#31RECOMBINANT
3scFv16COMPLEX#41RECOMBINANT
4Gastrin-17COMPLEX#51SYNTHETIC
5cholecystokinin type B receptorCOMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Baculovirus expression vector pFastBac1-HM274590
32Baculovirus expression vector pFastBac1-HM274590
44Baculovirus expression vector pFastBac1-HM274590
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: SPOT SCAN
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 1.75 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 354647 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 59.93 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00518674
ELECTRON MICROSCOPYf_angle_d1.05311771
ELECTRON MICROSCOPYf_chiral_restr0.05891339
ELECTRON MICROSCOPYf_plane_restr0.0081484
ELECTRON MICROSCOPYf_dihedral_angle_d14.10223096

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