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- PDB-8z8b: Cryo-EM structure of human HCAR1-Gi complex without ligand (apo state) -

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Basic information

Entry
Database: PDB / ID: 8z8b
TitleCryo-EM structure of human HCAR1-Gi complex without ligand (apo state)
Components
  • 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
  • single Fab chain (scFv16)
KeywordsMEMBRANE PROTEIN / hydroxycarboxylic acid receptor / Class A GPCR
Function / homology
Function and homology information


Hydroxycarboxylic acid-binding receptors / negative regulation of lipid catabolic process / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / 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 ...Hydroxycarboxylic acid-binding receptors / negative regulation of lipid catabolic process / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / 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 / chemokine-mediated signaling pathway / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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) / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / GDP binding / 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 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / sensory perception of taste / sperm principal piece / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / retina development in camera-type eye / GTPase binding / G protein activity / fibroblast proliferation / 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 / 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 / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / 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)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsGao, M. / Zang, S. / Zhu, Y. / Mao, C. / Zhang, Y. / Ma, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Signal / Year: 2026
Title: Structural insights into the activation mechanism of the human metabolite receptor HCAR1.
Authors: Mengru Gao / ShaoKun Zang / Yanqing Zhu / Kun Xi / Yage Du / Shizhuo Cheng / Luwei Miao / Yanhui Lu / Chunyou Mao / Yan Zhang / Xin Ma /
Abstract: Hydroxycarboxylic acid receptor 1 (HCAR1) is a class A G protein-coupled receptor (GPCR) that is activated by the endogenous metabolite l-lactate and that plays an important role in various metabolic ...Hydroxycarboxylic acid receptor 1 (HCAR1) is a class A G protein-coupled receptor (GPCR) that is activated by the endogenous metabolite l-lactate and that plays an important role in various metabolic and inflammatory disorders. HCAR1 uses distinct ligand recognition and self-activation mechanisms to mediate specific pathophysiological functions through Gα and β-arrestin signaling pathways. To support effective drug development targeting HCAR1, we investigated ligand recognition and activation mechanisms through cryo-electron microscopy (cryo-EM) structures of the HCAR1-Gα complex in the apo state or with l-lactate or with the synthetic agonist CHBA. Compared with other HCARs, HCAR1 has a more compact binding pocket, which is stabilized by three unique disulfide bonds. l-lactate exhibited a flexible binding mode and relatively weak intermolecular interactions, thus requiring millimolar concentrations for receptor activation. In contrast, the binding of CHBA was more stable because of its chlorinated benzene ring, thus resulting in improved agonist potency. Structural comparisons with HCAR2 identified critical residues that restrict the size of the binding pocket of HCAR1 and influence ligand selectivity. Self-activation of HCAR1 is driven by conformational rearrangements within extracellular loop 2, with Phe168 playing a pivotal role as the key agonist. Together, these results clarify the mechanisms underlying HCAR1 activation, self-activation, and ligand selectivity, providing a structural framework for the design of high-affinity, selective agonists and inverse agonists with minimized off-target effects.
History
DepositionApr 21, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 29, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Hydroxycarboxylic acid receptor 1
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
S: single Fab chain (scFv16)


Theoretical massNumber of molelcules
Total (without water)152,0085
Polymers152,0085
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 39338.254 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
#2: 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 / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: 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
#5: Antibody single Fab chain (scFv16)


Mass: 26610.615 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Cell (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper)
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 without ligand (apo state)
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 252930 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0069067
ELECTRON MICROSCOPYf_angle_d0.74412282
ELECTRON MICROSCOPYf_dihedral_angle_d14.4253242
ELECTRON MICROSCOPYf_chiral_restr0.051384
ELECTRON MICROSCOPYf_plane_restr0.0051561

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