+Open data
-Basic information
Entry | Database: PDB / ID: 8iy9 | ||||||
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Title | Structure of Niacin-GPR109A-G protein complex | ||||||
Components |
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Keywords | SIGNALING PROTEIN / GPCR / G protein | ||||||
Function / homology | Function and homology information positive regulation of adiponectin secretion / 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 ...positive regulation of adiponectin secretion / 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 / 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 insulin secretion / negative regulation of lipid catabolic process / G protein-coupled serotonin receptor binding / muscle contraction / locomotory behavior / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating 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 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cell junction / 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 / 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 / G alpha (i) signalling events / cell body / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / chemical synaptic transmission / postsynaptic membrane / Extra-nuclear estrogen signaling / cell population proliferation / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / dendrite / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.37 Å | ||||||
Authors | Yadav, M.K. / Sarma, P. / Chami, M. / Banerjee, R. / Shukla, A.K. | ||||||
Funding support | India, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8iy9.cif.gz | 224.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8iy9.ent.gz | 167.4 KB | Display | PDB format |
PDBx/mmJSON format | 8iy9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8iy9_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 8iy9_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 8iy9_validation.xml.gz | 42.9 KB | Display | |
Data in CIF | 8iy9_validation.cif.gz | 65.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/iy/8iy9 ftp://data.pdbj.org/pub/pdb/validation_reports/iy/8iy9 | HTTPS FTP |
-Related structure data
Related structure data | 35817MC 8iyhC 8iywC 8jerC 8jhnC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | 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: Escherichia coli (E. coli) / References: UniProt: P09471 |
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#2: Protein | 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873 |
#3: Protein | 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 |
-Antibody / Protein / Non-polymers , 3 types, 3 molecules HR
#4: 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) |
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#5: Protein | 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, GPR109A, HCA2, HM74A, NIACR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08173, UniProt: Q8TDS4 |
#6: Chemical | ChemComp-NIO / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Molecular weight | Experimental value: NO | |||||||||||||||||||||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | |||||||||||||||||||||||||||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||||||||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Microscopy | Model: TFS GLACIOS |
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 55 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
Image scans | Movie frames/image: 40 |
-Processing
EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 7027107 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.37 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1011301 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||
Atomic model building | Accession code: AF-Q8TDS4-F1 / Source name: AlphaFold / Type: in silico model | ||||||||||||||||||||||||
Refine LS restraints |
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