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Yorodumi- EMDB-36312: Cryo-EM structure of compound 9n and niacin bound ketone body rec... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36312 | |||||||||
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Title | Cryo-EM structure of compound 9n and niacin bound ketone body receptor HCAR2-Gi signaling complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Complex / Agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / positive regulation of neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of adiponectin secretion / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / positive regulation of neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of adiponectin secretion / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / negative regulation of lipid catabolic process / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Regulation of insulin secretion / G protein-coupled receptor binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / response to peptide hormone / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / cell junction / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / midbody / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / centrosome / synapse / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.17 Å | |||||||||
Authors | Zhao C / Tian XW / Liu Y / Cheng L / Yan W / Shao ZH | |||||||||
Funding support | China, 1 items
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Citation | Journal: Mol Cell / Year: 2023 Title: Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation. Authors: Chang Zhao / Heli Wang / Ying Liu / Lin Cheng / Bo Wang / Xiaowen Tian / Hong Fu / Chao Wu / Ziyan Li / Chenglong Shen / Jingjing Yu / Shengyong Yang / Hongbo Hu / Ping Fu / Liang Ma / ...Authors: Chang Zhao / Heli Wang / Ying Liu / Lin Cheng / Bo Wang / Xiaowen Tian / Hong Fu / Chao Wu / Ziyan Li / Chenglong Shen / Jingjing Yu / Shengyong Yang / Hongbo Hu / Ping Fu / Liang Ma / Chuanxin Wang / Wei Yan / Zhenhua Shao / Abstract: Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 ...Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G protein or β-arrestin effectors. Here, we characterize compound 9n as a G-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G pathway. Furthermore, four structures of HCAR2-G complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_36312.map.gz | 59.5 MB | EMDB map data format | |
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Header (meta data) | emd-36312-v30.xml emd-36312.xml | 20.7 KB 20.7 KB | Display Display | EMDB header |
Images | emd_36312.png | 46.7 KB | ||
Others | emd_36312_additional_1.map.gz | 59.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36312 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36312 | HTTPS FTP |
-Validation report
Summary document | emd_36312_validation.pdf.gz | 490.8 KB | Display | EMDB validaton report |
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Full document | emd_36312_full_validation.pdf.gz | 490.3 KB | Display | |
Data in XML | emd_36312_validation.xml.gz | 6.3 KB | Display | |
Data in CIF | emd_36312_validation.cif.gz | 7.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36312 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36312 | HTTPS FTP |
-Related structure data
Related structure data | 8jiiMC 8jhyC 8jilC 8jimC C: citing same article (ref.) M: atomic model generated by this map |
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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_36312.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: The consensus map
File | emd_36312_additional_1.map | ||||||||||||
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Annotation | The consensus map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : HCA2 in complex with Gi heterotrimer
+Supramolecule #1: HCA2 in complex with Gi heterotrimer
+Supramolecule #2: Nicotinic acid receptor in complex with Gi heterotrimer
+Supramolecule #3: scFv16
+Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #4: scFv16
+Macromolecule #5: Hydroxycarboxylic acid receptor 2
+Macromolecule #6: NICOTINIC ACID
+Macromolecule #7: CHOLESTEROL
+Macromolecule #8: 7-methyl-N-[(2R)-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyr...
+Macromolecule #9: water
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 65.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175324 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |