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- PDB-7mby: Human Cholecystokinin 1 receptor (CCK1R) Gq chimera (mGsqi) complex -

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Basic information

Entry
Database: PDB / ID: 7mby
TitleHuman Cholecystokinin 1 receptor (CCK1R) Gq chimera (mGsqi) complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Cholecystokinin receptor type A
  • Cholecystokinin-8
KeywordsMEMBRANE PROTEIN/SIGNALING PROTEIN / GPCR / MEMBRANE PROTEIN / MEMBRANE PROTEIN-SIGNALING PROTEIN complex
Function / homology
Function and homology information


cholecystokinin receptor activity / cholecystokinin signaling pathway / regulation of hormone secretion / neuropeptide hormone activity / 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 ...cholecystokinin receptor activity / cholecystokinin signaling pathway / regulation of hormone secretion / neuropeptide hormone activity / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / alkylglycerophosphoethanolamine phosphodiesterase activity / photoreceptor outer segment membrane / eating behavior / peptide hormone receptor binding / spectrin binding / PKA activation in glucagon signalling / peptide hormone binding / hair follicle placode formation / developmental growth / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / renal water homeostasis / Hedgehog 'off' state / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cellular response to forskolin / cellular response to hormone stimulus / forebrain development / regulation of mitotic spindle organization / digestion / cardiac muscle cell apoptotic process / cellular response to glucagon stimulus / adenylate cyclase activator activity / regulation of insulin secretion / photoreceptor inner segment / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / axonogenesis / Peptide ligand-binding receptors / trans-Golgi network membrane / Regulation of insulin secretion / G protein-coupled receptor binding / negative regulation of inflammatory response to antigenic stimulus / peptide binding / neuron migration / bone development / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein activity / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / platelet aggregation / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / cognition / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / 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 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / 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 / GDP binding / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding
Similarity search - Function
Cholecystokinin-like / Gastrin/cholecystokinin peptide hormone / Gastrin/cholecystokinin, conserved site / Gastrin/cholecystokinin family / Gastrin / cholecystokinin family signature. / gastrin / cholecystokinin / caerulein family / Cholecystokinin receptor type A / Cholecystokinin A receptor, N-terminal / Cholecystokinin A receptor, N-terminal domain superfamily / Cholecystokinin A receptor, N-terminal ...Cholecystokinin-like / Gastrin/cholecystokinin peptide hormone / Gastrin/cholecystokinin, conserved site / Gastrin/cholecystokinin family / Gastrin / cholecystokinin family signature. / gastrin / cholecystokinin / caerulein family / Cholecystokinin receptor type A / Cholecystokinin A receptor, N-terminal / Cholecystokinin A receptor, N-terminal domain superfamily / Cholecystokinin A receptor, N-terminal / Cholecystokinin receptor / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
CHOLESTEROL HEMISUCCINATE / Cholecystokinin / Cholecystokinin receptor type A / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.44 Å
AuthorsMobbs, J.I. / Belousoff, M.J. / Danev, R. / Thal, D.M. / Sexton, P.M.
Funding support Australia, Japan, 3items
OrganizationGrant numberCountry
Australian Research Council (ARC) Australia
National Health and Medical Research Council (NHMRC, Australia) Australia
Japan Science and Technology Japan
Citation
Journal: PLoS Biol / Year: 2021
Title: Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.
Authors: Jesse I Mobbs / Matthew J Belousoff / Kaleeckal G Harikumar / Sarah J Piper / Xiaomeng Xu / Sebastian G B Furness / Hari Venugopal / Arthur Christopoulos / Radostin Danev / Denise Wootten / ...Authors: Jesse I Mobbs / Matthew J Belousoff / Kaleeckal G Harikumar / Sarah J Piper / Xiaomeng Xu / Sebastian G B Furness / Hari Venugopal / Arthur Christopoulos / Radostin Danev / Denise Wootten / David M Thal / Laurence J Miller / Patrick M Sexton /
Abstract: G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic ...G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-α5 helix (αH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs αH5 displaying a conformation that arises from "unwinding" of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.
#1: Journal: Biorxiv / Year: 2021
Title: Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins: insight into mechanisms of G protein selectivity
Authors: Mobbs, J. / Belousoff, M.J. / Harikumar, K.G. / Piper, S.J. / Xu, X. / Furness, S.G.B. / Venugopal, H. / Christopoulos, A. / Danev, R. / Wootten, D. / Thal, D.M. / Miller, L.J. / Sexton, P.M.
History
DepositionApr 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 26, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
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
P: Cholecystokinin-8
R: Cholecystokinin receptor type A
A: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,with certain residues mutated to match Guanine nucleotide-binding protein G(q) subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,8076
Polymers123,3205
Non-polymers4871
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 BGA

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


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311
#2: 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
#5: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,with certain residues mutated to match Guanine nucleotide-binding protein G(q) subunit / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / ...Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / Adenylate cyclase-stimulating G alpha protein


Mass: 29144.971 Da / Num. of mol.: 1
Mutation: R39, L41, K343, V346, D347, I358, K380, L384, Q385, N387, E390, N392, V394 represent residues from G(q)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAS, GNAS1, GSP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63096, UniProt: P63092

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Protein/peptide / Protein / Non-polymers , 3 types, 3 molecules PR

#3: Protein/peptide Cholecystokinin-8 / CCK-8


Mass: 1142.262 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P06307
#4: Protein Cholecystokinin receptor type A / CCK-A receptor / CCK-AR / Cholecystokinin-1 receptor / CCK1-R


Mass: 47754.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCKAR, CCKRA / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P32238
#6: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4

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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
IDNameTypeDetailsEntity IDParent-IDSource
1CCK1R/CCK-8/mGsqi complexCOMPLEXCCK1R/CCK-8/mGsqi/Gb1/Gg2/scfv16#1-#50MULTIPLE SOURCES
2G protein subunit beta-1COMPLEX#11RECOMBINANT
3G(sqi)-alpha/G protein subunit gamma-2COMPLEX#2, #51RECOMBINANT
4CCK1RCOMPLEX#41RECOMBINANT
5CCK-8COMPLEX#31SYNTHETIC
6scFv16COMPLEX1RECOMBINANT
Molecular weightValue: 150 kDa/nm / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Rattus norvegicus (Norway rat)10116
23Homo sapiens (human)9606
34Homo sapiens (human)9606
45Homo sapiens (human)9606
56Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Trichoplusia ni (cabbage looper)7111
23Trichoplusia ni (cabbage looper)7111
34Trichoplusia ni (cabbage looper)7111
46Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.4
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 63.9 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 444000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0057021
ELECTRON MICROSCOPYf_angle_d0.9149543
ELECTRON MICROSCOPYf_dihedral_angle_d11.9442447
ELECTRON MICROSCOPYf_chiral_restr0.0581123
ELECTRON MICROSCOPYf_plane_restr0.0071191

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