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- PDB-8iyh: Structure of MK6892-GPR109A-G-protein complex -

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Basic information

Entry
Database: PDB / ID: 8iyh
TitleStructure of MK6892-GPR109A-G-protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Hydroxycarboxylic acid receptor 2
  • ScFv16 Antibody
KeywordsSIGNALING PROTEIN / GPCR / G protein
Function / homology
Function and homology information


nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / Muscarinic acetylcholine receptors / neutrophil apoptotic process / G protein-coupled acetylcholine receptor activity / positive regulation of neutrophil apoptotic process / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / Class A/1 (Rhodopsin-like receptors) / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / Muscarinic acetylcholine receptors / neutrophil apoptotic process / G protein-coupled acetylcholine receptor activity / positive regulation of neutrophil apoptotic process / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / Class A/1 (Rhodopsin-like receptors) / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / G protein-coupled serotonin receptor activity / vesicle docking involved in exocytosis / positive regulation of adiponectin secretion / regulation of locomotion / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / negative regulation of lipid catabolic process / negative regulation of insulin secretion / G protein-coupled serotonin receptor binding / muscle contraction / locomotory behavior / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / 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 / 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 / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / cell junction / 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 / cell body / 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 / chemical synaptic transmission / G alpha (q) signalling events / postsynaptic membrane / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Muscarinic acetylcholine receptor M4 / : / Muscarinic acetylcholine receptor family / 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 ...Muscarinic acetylcholine receptor M4 / : / Muscarinic acetylcholine receptor family / 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
Chem-FI7 / Muscarinic acetylcholine receptor M4 / Guanine nucleotide-binding protein G(o) 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 / Hydroxycarboxylic acid receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYadav, M.K. / Sarma, P. / Chami, M. / Banerjee, R. / Shukla, A.K.
Funding support India, 1items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)BT/PR29041/BRB/10/1697/20 India
CitationJournal: Nat Commun / Year: 2024
Title: Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution.
Authors: Manish K Yadav / Parishmita Sarma / Jagannath Maharana / Manisankar Ganguly / Sudha Mishra / Nashrah Zaidi / Annu Dalal / Vinay Singh / Sayantan Saha / Gargi Mahajan / Saloni Sharma / ...Authors: Manish K Yadav / Parishmita Sarma / Jagannath Maharana / Manisankar Ganguly / Sudha Mishra / Nashrah Zaidi / Annu Dalal / Vinay Singh / Sayantan Saha / Gargi Mahajan / Saloni Sharma / Mohamed Chami / Ramanuj Banerjee / Arun K Shukla /
Abstract: The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. ...The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor.
History
DepositionApr 4, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 6, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
B: Guanine nucleotide-binding protein G(o) subunit alpha
D: Hydroxycarboxylic acid receptor 2
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: ScFv16 Antibody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,0726
Polymers147,6855
Non-polymers3861
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 ABG

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


Mass: 38534.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Escherichia coli (E. coli) / References: UniProt: P62873
#2: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 27024.762 Da / Num. of mol.: 1 / Mutation: G42D,E43N,A227D,G230D,I332A,V335I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P09471
#4: 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 / Antibody / Non-polymers , 3 types, 3 molecules DH

#3: Protein Hydroxycarboxylic acid receptor 2


Mass: 47798.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRM4, HCAR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08173, UniProt: Q8TDS4
#5: Antibody ScFv16 Antibody


Mass: 26466.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)
#6: Chemical ChemComp-FI7 / 2-[[2,2-dimethyl-3-[3-(5-oxidanylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic acid


Mass: 386.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N4O5 / 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-IDSourceDetails
1Structure of MK6892-GPR109A-G-protein complexCOMPLEX#1-#50MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(o) subunit alphaCOMPLEX#11RECOMBINANTThis is a variant of Guanine nucleotide-binding protein G(o) subunit alpha called the "mini G(o) alpha"
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#41RECOMBINANT
5ScFv16 Antibody fragmentCOMPLEX#51RECOMBINANT
6Hydroxycarboxylic acid receptor 2/GPR109ACOMPLEX#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
53Homo sapiens (human)9606
64Mus musculus (house mouse)10090
75Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (E. coli)562
32Spodoptera frugiperda (fall armyworm)7108
53Spodoptera frugiperda (fall armyworm)7108
64Escherichia coli (E. coli)562
75Spodoptera frugiperda (fall armyworm)7108
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

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 55 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4particle selection
7Cootmodel fitting
9PHENIXmodel refinement
12cryoSPARC4classification
13cryoSPARC43D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 9068321
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1200513 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 8IY9

8iy9


Accession code: 8IY9 / Source name: PDB / Type: experimental model

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