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- PDB-8j6l: Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi prot... -

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Basic information

Entry
Database: PDB / ID: 8j6l
TitleCryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound niacin
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Hydroxycarboxylic acid receptor 2,hydroxycarboxylic acid receptor 2
  • SVF16
KeywordsMEMBRANE PROTEIN / hydroxycarboxylic acid receptor 2 / GPCR / niacin / MK-6892 / GSK256073
Function / homology
Function and homology information


nicotinic acid receptor activity / neutrophil apoptotic process / Hydroxycarboxylic acid-binding receptors / positive regulation of neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration ...nicotinic acid receptor activity / neutrophil apoptotic process / Hydroxycarboxylic acid-binding receptors / positive regulation of neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / 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 / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / GDP binding / Vasopressin regulates renal water homeostasis via Aquaporins / cell junction / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane
Similarity search - Function
: / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain ...: / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
NICOTINIC ACID / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Hydroxycarboxylic acid receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsYuan, Q. / Zhu, S. / Duan, J. / Xu, H.E. / Duan, X.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
Ministry of Science and Technology (MoST, China) China
CitationJournal: Cell Rep / Year: 2023
Title: Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2.
Authors: Shengnan Zhu / Qingning Yuan / Xinzhu Li / Xinheng He / Shiyi Shen / Dongxue Wang / Junrui Li / Xi Cheng / Xiaoqun Duan / H Eric Xu / Jia Duan /
Abstract: Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. ...Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created. However, the activation mechanism of HCAR2 by niacin and these new agonists is not well understood. Here, we present three cryoelectron microscopy structures of Gi-coupled HCAR2 bound to niacin, MK-6892, and GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced by aromatic amino acid clusters (W91, H161, W188, H189, and F193) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111 and Y284, unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs.
History
DepositionApr 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release
Revision 1.0Apr 3, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 3, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 3, 2024Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 3, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 3, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 25, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1Jun 25, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: SVF16
R: Hydroxycarboxylic acid receptor 2,hydroxycarboxylic acid receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,7486
Polymers170,6255
Non-polymers1231
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 40095.797 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 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7729.947 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

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Antibody / Protein / Non-polymers , 3 types, 3 molecules HR

#4: Antibody SVF16


Mass: 26277.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Hydroxycarboxylic acid receptor 2,hydroxycarboxylic acid receptor 2 / G-protein coupled receptor 109A / G-protein coupled receptor HM74A / Niacin receptor 1 / Nicotinic ...G-protein coupled receptor 109A / G-protein coupled receptor HM74A / Niacin receptor 1 / Nicotinic acid receptor


Mass: 56107.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCAR2, GPR109A, HCA2, HM74A, NIACR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TDS4
#6: Chemical ChemComp-NIO / NICOTINIC ACID


Mass: 123.109 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H5NO2

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: complex of hydroxycarboxylic acid receptor 2 with MK-6892
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 18000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 510037 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029048
ELECTRON MICROSCOPYf_angle_d0.50212258
ELECTRON MICROSCOPYf_dihedral_angle_d3.6721221
ELECTRON MICROSCOPYf_chiral_restr0.0391389
ELECTRON MICROSCOPYf_plane_restr0.0051546

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