+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36010 | |||||||||
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Title | Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | hydroxycarboxylic acid receptor / Niacin / compound 9n / Class A GPCR / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of neutrophil apoptotic process / positive regulation of adiponectin secretion / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of neutrophil apoptotic process / positive regulation of adiponectin secretion / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / negative regulation of lipid catabolic process / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / 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 / response to peptide hormone / 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 / GDP binding / 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 / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell cycle / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.55 Å | |||||||||
Authors | Mao C / Gao M / Zang S / Zhu Y / Ma X / Zhang Y | |||||||||
Funding support | 1 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Orthosteric and allosteric modulation of human HCAR2 signaling complex. Authors: Chunyou Mao / Mengru Gao / Shao-Kun Zang / Yanqing Zhu / Dan-Dan Shen / Li-Nan Chen / Liu Yang / Zhiwei Wang / Huibing Zhang / Wei-Wei Wang / Qingya Shen / Yanhui Lu / Xin Ma / Yan Zhang / Abstract: Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors ...Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_36010.map.gz | 29 MB | EMDB map data format | |
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Header (meta data) | emd-36010-v30.xml emd-36010.xml | 21 KB 21 KB | Display Display | EMDB header |
Images | emd_36010.png | 80 KB | ||
Filedesc metadata | emd-36010.cif.gz | 6.8 KB | ||
Others | emd_36010_half_map_1.map.gz emd_36010_half_map_2.map.gz | 32.9 MB 32.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36010 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36010 | HTTPS FTP |
-Related structure data
Related structure data | 8j6pMC 8j6qC 8j6rC 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_36010.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.93 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36010_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36010_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Cryo-EM structure of the Niacin, compound 9n-bound human HCAR2-Gi...
+Supramolecule #1: Cryo-EM structure of the Niacin, compound 9n-bound human HCAR2-Gi...
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: single Fab chain (scFv16)
+Macromolecule #5: Hydroxycarboxylic acid receptor 2
+Macromolecule #6: 7-methyl-N-[(2R)-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyr...
+Macromolecule #7: CHOLESTEROL
+Macromolecule #8: NICOTINIC ACID
+Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #10: water
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 15 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 52.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 321148 |