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- PDB-9izd: Cryo-EM structure of human HCAR1-Gi complex with CHBA -

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Entry
Database: PDB / ID: 9izd
TitleCryo-EM structure of human HCAR1-Gi complex with CHBA
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Hydroxycarboxylic acid receptor 1
  • scFv16
KeywordsMEMBRANE PROTEIN / complex
Function / homology
Function and homology information


Hydroxycarboxylic acid-binding receptors / negative regulation of lipid catabolic process / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway ...Hydroxycarboxylic acid-binding receptors / negative regulation of lipid catabolic process / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / neuropeptide signaling pathway / Regulation of insulin secretion / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / GDP binding / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / GTPase binding / G protein activity / midbody / Ca2+ pathway / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / ciliary basal body / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / GTP binding / protein-containing complex binding / magnesium ion binding / signal transduction / extracellular exosome / membrane / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain ...: / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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
: / 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 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsXin, P. / Fang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: PLoS Biol / Year: 2025
Title: Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity.
Authors: Xin Pan / Fang Ye / Peiruo Ning / Yiping Yu / Zhiyi Zhang / Jingxuan Wang / Geng Chen / Zhangsong Wu / Chen Qiu / Jiancheng Li / Bangning Chen / Lizhe Zhu / Chungen Qian / Kaizheng Gong / Yang Du /
Abstract: Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate receptor or GPR81, is a class A G-protein-coupled receptor with key roles in regulating lipid metabolism, neuroprotection, ...Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate receptor or GPR81, is a class A G-protein-coupled receptor with key roles in regulating lipid metabolism, neuroprotection, angiogenesis, cardiovascular function, and inflammatory response in humans. HCAR1 is highly expressed in numerous types of cancer cells, where it participates in controlling cancer cell metabolism and defense mechanisms, rendering it an appealing target for cancer therapy. However, the molecular basis of HCAR1-mediated signaling remains poorly understood. Here, we report four cryo-EM structures of human HCAR1 and HCAR2 in complex with the Gi1 protein, in which HCAR1 binds to the subtype-specific agonist CHBA (3.16 Å) and apo form (3.36 Å), and HCAR2 binds to the subtype-specific agonists MK-1903 (2.68 Å) and SCH900271 (3.06 Å). Combined with mutagenesis and cellular functional assays, we elucidate the mechanisms underlying ligand recognition, receptor activation, and G protein coupling of HCAR1. More importantly, the key residues that determine ligand selectivity between HCAR1 and HCAR2 are clarified. On this basis, we further summarize the structural features of agonists that match the orthosteric pockets of HCAR1 and HCAR2. These structural insights are anticipated to greatly accelerate the development of novel HCAR1-targeted drugs, offering a promising avenue for the treatment of various diseases.
History
DepositionAug 1, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Jul 16, 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

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Assembly

Deposited unit
A: Hydroxycarboxylic acid receptor 1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(i) subunit alpha-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,6356
Polymers141,4625
Non-polymers1731
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 37069.543 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) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40153.672 Da / Num. of mol.: 1 / Mutation: G203A, A326S
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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6218.162 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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Protein / Antibody / Non-polymers , 3 types, 3 molecules AS

#1: Protein Hydroxycarboxylic acid receptor 1 / G-protein coupled receptor 104 / G-protein coupled receptor 81


Mass: 31596.498 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCAR1, GPR104, GPR81, HCA1, FKSG80 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BXC0
#5: Antibody scFv16


Mass: 26424.385 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)
#6: Chemical ChemComp-A1D71 / 3-chloranyl-5-oxidanyl-benzoic acid / Hydantoin-5-acetic acid


Mass: 172.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H5ClO3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: Cryo-EM structure of human HCAR1-Gi complex with CHBA / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 56 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: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 518325 / Symmetry type: POINT

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