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- EMDB-36902: Cryo-EM structure of GSK256073 bound human hydroxy-carboxylic aci... -
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Basic information
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Title | Cryo-EM structure of GSK256073 bound human hydroxy-carboxylic acid receptor 2 (Local refinement) | |||||||||
![]() | sharpening map | |||||||||
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![]() | GPCR / G-Protein / MEMBRANE PROTEIN / signaling | |||||||||
Function / homology | ![]() 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 / negative regulation of lipid catabolic process / cell junction / G alpha (i) signalling events / G protein-coupled receptor signaling pathway / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.74 Å | |||||||||
![]() | Park JH / Ishimoto N / Park SY | |||||||||
Funding support | 1 items
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![]() | ![]() Title: Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2. Authors: Jae-Hyun Park / Kouki Kawakami / Naito Ishimoto / Tatsuya Ikuta / Mio Ohki / Toru Ekimoto / Mitsunori Ikeguchi / Dong-Sun Lee / Young-Ho Lee / Jeremy R H Tame / Asuka Inoue / Sam-Yong Park / ![]() ![]() Abstract: Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with ...Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced G-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-G signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 28.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.3 KB 18.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 7 KB | Display | ![]() |
Images | ![]() | 72.6 KB | ||
Masks | ![]() | 30.5 MB | ![]() | |
Filedesc metadata | ![]() | 5.9 KB | ||
Others | ![]() ![]() ![]() | 15.2 MB 28.3 MB 28.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 817.6 KB | Display | ![]() |
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Full document | ![]() | 817.2 KB | Display | |
Data in XML | ![]() | 13.5 KB | Display | |
Data in CIF | ![]() | 17.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8k5dMC ![]() 8i7vC ![]() 8i7wC ![]() 8k5bC ![]() 8k5cC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | sharpening map | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.245 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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-Additional map: map
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Sample components
-Entire : GSK256073 bound human hydroxy-carboxylic acid receptor 2
Entire | Name: GSK256073 bound human hydroxy-carboxylic acid receptor 2 |
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Components |
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-Supramolecule #1: GSK256073 bound human hydroxy-carboxylic acid receptor 2
Supramolecule | Name: GSK256073 bound human hydroxy-carboxylic acid receptor 2 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 150 KDa |
-Macromolecule #1: Human hydroxycarboxylic acid receptor 2
Macromolecule | Name: Human hydroxycarboxylic acid receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 54.320297 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GPGAPADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKV KEAQAAAEQL KTTRNAYIQK YLEFMNRHHL QDHFLEIDKK NCCVFRDDFI VKVLPPVLGL EFIFGLLGNG L ALWIFCFH ...String: GPGAPADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKV KEAQAAAEQL KTTRNAYIQK YLEFMNRHHL QDHFLEIDKK NCCVFRDDFI VKVLPPVLGL EFIFGLLGNG L ALWIFCFH LKSWKSSRIF LFNLAVADFL LIICLPFLMD NYVRRWDWKF GDIPCRLMLF MLAMNRQGSI IFLTVVAVDR YF RVVHPHH ALNKISNRTA AIISCLLWGI TIGLTVHLLK KKMPIQNGGA NLCSSFSICH TFQWHEAMFL LEFFLPLGII LFC SARIIW SLRQRQMDRH AKIKRAITFI MVVAIVFVIC FLPSVVVRIR IFWLLHTSGT QNCEVYRSVD LAFFITLSFT YMNS MLDPV VYYFSSPSFP NFFSTLINRC LQRKMTGEPD NNRSTSVELT GDPNKTRGAP EALMANSGEP WSPSYLGPTS P UniProtKB: Hydroxycarboxylic acid receptor 2 |
-Macromolecule #2: 8-chloranyl-3-pentyl-7H-purine-2,6-dione
Macromolecule | Name: 8-chloranyl-3-pentyl-7H-purine-2,6-dione / type: ligand / ID: 2 / Number of copies: 1 / Formula: OKL |
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Molecular weight | Theoretical: 256.689 Da |
Chemical component information | ![]() ChemComp-OKL: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL |
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Output model | ![]() PDB-8k5d: |