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- PDB-7cky: Cryo-EM structure of PW0464 bound dopamine receptor DRD1-Gs signa... -

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Basic information

Entry
Database: PDB / ID: 7cky
TitleCryo-EM structure of PW0464 bound dopamine receptor DRD1-Gs signaling complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • D(1A) dopamine receptor
  • Nanobody 35
KeywordsCELL CYCLE / signaling complex
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / sensitization / operant conditioning / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / modification of postsynaptic structure / dopamine binding / heterotrimeric G-protein binding ...dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / sensitization / operant conditioning / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / modification of postsynaptic structure / dopamine binding / heterotrimeric G-protein binding / G protein-coupled receptor complex / peristalsis / regulation of dopamine metabolic process / grooming behavior / phospholipase C-activating dopamine receptor signaling pathway / positive regulation of neuron migration / habituation / dopamine transport / positive regulation of potassium ion transport / astrocyte development / conditioned taste aversion / striatum development / dentate gyrus development / maternal behavior / arrestin family protein binding / non-motile cilium / long-term synaptic depression / mating behavior / adult walking behavior / ciliary membrane / G protein-coupled dopamine receptor signaling pathway / temperature homeostasis / D-glucose import / transmission of nerve impulse / dopamine metabolic process / PKA activation in glucagon signalling / behavioral response to cocaine / hair follicle placode formation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / behavioral fear response / developmental growth / neuronal action potential / G-protein alpha-subunit binding / D1 dopamine receptor binding / intracellular transport / renal water homeostasis / Hedgehog 'off' state / prepulse inhibition / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / GABA-ergic synapse / cellular response to glucagon stimulus / synapse assembly / adenylate cyclase activator activity / presynaptic modulation of chemical synaptic transmission / response to amphetamine / regulation of insulin secretion / positive regulation of synaptic transmission, glutamatergic / positive regulation of release of sequestered calcium ion into cytosol / trans-Golgi network membrane / synaptic transmission, glutamatergic / long-term synaptic potentiation / G protein-coupled receptor activity / negative regulation of inflammatory response to antigenic stimulus / bone development / regulation of protein phosphorylation / visual learning / 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 / cilium / G protein-coupled acetylcholine receptor signaling pathway / 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 / memory / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / 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 / vasodilation / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / protein import into nucleus
Similarity search - Function
Dopamine D1 receptor / Dopamine receptor family / G-protein alpha subunit, group S / 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 ...Dopamine D1 receptor / Dopamine receptor family / G-protein alpha subunit, group S / 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 / Chem-G3U / D(1A) dopamine receptor / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYan, W. / Shao, Z.
CitationJournal: Cell / Year: 2021
Title: Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes.
Authors: Peng Xiao / Wei Yan / Lu Gou / Ya-Ni Zhong / Liangliang Kong / Chao Wu / Xin Wen / Yuan Yuan / Sheng Cao / Changxiu Qu / Xin Yang / Chuan-Cheng Yang / Anjie Xia / Zhenquan Hu / Qianqian ...Authors: Peng Xiao / Wei Yan / Lu Gou / Ya-Ni Zhong / Liangliang Kong / Chao Wu / Xin Wen / Yuan Yuan / Sheng Cao / Changxiu Qu / Xin Yang / Chuan-Cheng Yang / Anjie Xia / Zhenquan Hu / Qianqian Zhang / Yong-Hao He / Dao-Lai Zhang / Chao Zhang / Gui-Hua Hou / Huanxiang Liu / Lizhe Zhu / Ping Fu / Shengyong Yang / Daniel M Rosenbaum / Jin-Peng Sun / Yang Du / Lei Zhang / Xiao Yu / Zhenhua Shao /
Abstract: Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five ...Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
History
DepositionJul 20, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 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

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Structure visualization

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Assembly

Deposited unit
A: 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
R: D(1A) dopamine receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,9307
Polymers158,1545
Non-polymers7762
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14920 Å2
ΔGint-68 kcal/mol
Surface area39180 Å2

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Components

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

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


Mass: 45769.570 Da / Num. of mol.: 1 / Mutation: S205T,G226A,A366S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38257.770 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
#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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein , 2 types, 2 molecules NR

#4: Antibody Nanobody 35


Mass: 16926.076 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#5: Protein D(1A) dopamine receptor / Dopamine D1 receptor


Mass: 49339.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DRD1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21728

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Non-polymers , 2 types, 2 molecules

#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-G3U / 6-[4-[3-[bis(fluoranyl)methoxy]pyridin-2-yl]oxy-2-methyl-phenyl]-1,5-dimethyl-pyrimidine-2,4-dione


Mass: 389.353 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17F2N3O4 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1Complex structure-3COMPLEX#1-#50RECOMBINANT
2Guanine nucleotide-binding protein G(s) subunit alpha, beta, gammaCOMPLEX#1-#31RECOMBINANT
3Nanobody 35COMPLEX#41RECOMBINANT
4D(1A) dopamine receptorCOMPLEX#51RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Lama glama (llama)9844
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Escherichia coli (E. coli)562
44Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 64 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 672934 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028299
ELECTRON MICROSCOPYf_angle_d0.44811263
ELECTRON MICROSCOPYf_dihedral_angle_d13.2111136
ELECTRON MICROSCOPYf_chiral_restr0.0731281
ELECTRON MICROSCOPYf_plane_restr0.0031423

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