+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-35822 | |||||||||
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Title | Structure of MK6892-GPR109A-G-protein complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | GPCR / G protein / SIGNALING 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 / 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 / positive regulation of neutrophil apoptotic process ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / Muscarinic acetylcholine receptors / neutrophil apoptotic process / G protein-coupled acetylcholine receptor activity / 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 / positive regulation of neutrophil apoptotic process / G protein-coupled serotonin receptor activity / regulation of locomotion / positive regulation of adiponectin secretion / dopamine receptor signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / G protein-coupled serotonin receptor binding / negative regulation of lipid catabolic process / muscle contraction / G-protein beta/gamma-subunit complex binding / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / cell junction / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / chemical synaptic transmission / G alpha (s) signalling events / postsynaptic membrane / G alpha (q) signalling events / 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 | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Yadav MK / Sarma P / Chami M / Banerjee R / Shukla AK | |||||||||
Funding support | India, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_35822.map.gz | 85.9 MB | EMDB map data format | |
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Header (meta data) | emd-35822-v30.xml emd-35822.xml | 23.5 KB 23.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_35822_fsc.xml | 9.4 KB | Display | FSC data file |
Images | emd_35822.png | 97.9 KB | ||
Filedesc metadata | emd-35822.cif.gz | 7.1 KB | ||
Others | emd_35822_half_map_1.map.gz emd_35822_half_map_2.map.gz | 84.6 MB 84.6 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-35822 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35822 | HTTPS FTP |
-Related structure data
Related structure data | 8iyhMC 8iy9C 8iywC 8jerC 8jhnC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_35822.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.0975 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_35822_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_35822_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Structure of MK6892-GPR109A-G-protein complex
+Supramolecule #1: Structure of MK6892-GPR109A-G-protein complex
+Supramolecule #2: Guanine nucleotide-binding protein G(o) subunit alpha
+Supramolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Supramolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Supramolecule #5: ScFv16 Antibody fragment
+Supramolecule #6: Hydroxycarboxylic acid receptor 2/GPR109A
+Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #2: Guanine nucleotide-binding protein G(o) subunit alpha
+Macromolecule #3: Hydroxycarboxylic acid receptor 2
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #5: ScFv16 Antibody
+Macromolecule #6: 2-[[2,2-dimethyl-3-[3-(5-oxidanylpyridin-2-yl)-1,2,4-oxadiazol-5-...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | TFS GLACIOS |
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Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm |
Sample stage | Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 55.0 e/Å2 |