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- PDB-8zbw: Cryo-EM structure of formyl peptide receptor 2/C1R receptor in co... -

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Entry
Database: PDB / ID: 8zbw
TitleCryo-EM structure of formyl peptide receptor 2/C1R receptor in complex with Gi
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-2
  • N-formyl peptide receptor 2
KeywordsSTRUCTURAL PROTEIN / Cryo-EM / formyl peptide receptor 2 / C1R
Function / homology
Function and homology information


N-formyl peptide receptor activity / complement receptor activity / immune response-regulating cell surface receptor signaling pathway / scavenger receptor binding / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / RAGE receptor binding / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / positive regulation of urine volume ...N-formyl peptide receptor activity / complement receptor activity / immune response-regulating cell surface receptor signaling pathway / scavenger receptor binding / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / RAGE receptor binding / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / positive regulation of urine volume / complement receptor mediated signaling pathway / positive regulation of neural precursor cell proliferation / positive regulation of monocyte chemotaxis / positive regulation of innate immune response / negative regulation of synaptic transmission / Formyl peptide receptors bind formyl peptides and many other ligands / cargo receptor activity / positive chemotaxis / gamma-aminobutyric acid signaling pathway / regulation of calcium ion transport / tertiary granule membrane / negative regulation of apoptotic signaling pathway / ficolin-1-rich granule membrane / neuronal dense core vesicle / specific granule membrane / Adenylate cyclase inhibitory pathway / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of superoxide anion generation / response to nutrient / astrocyte activation / receptor-mediated endocytosis / positive regulation of phagocytosis / hippocampal mossy fiber to CA3 synapse / Regulation of insulin secretion / microglial cell activation / calcium-mediated signaling / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of inflammatory response / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / cellular response to amyloid-beta / chemotaxis / 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 / 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 / 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 activity / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / amyloid-beta binding / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / cell body / GTPase binding / Ca2+ pathway / fibroblast proliferation / midbody / 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 / negative regulation of neuron apoptotic process / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway
Similarity search - Function
Formyl peptide receptor-related / 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 ...Formyl peptide receptor-related / 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
: / Guanine nucleotide-binding protein G(i) subunit alpha-2 / N-formyl peptide receptor 2 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsZhou, Q. / Lin, S. / Li, G.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Acta Pharmacol Sin / Year: 2025
Title: Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.
Authors: Wen-Sheng Yang / Qing Liu / Yang Li / Guan-Yi Li / Shi Lin / Jie Li / Lin-Yu Li / Yuan Li / Xi-Lin Ge / Xiao-Zhen Wang / Wei Wu / Jun Yan / Guang-Fei Wang / Qing-Tong Zhou / Qiang Liu / Ming- ...Authors: Wen-Sheng Yang / Qing Liu / Yang Li / Guan-Yi Li / Shi Lin / Jie Li / Lin-Yu Li / Yuan Li / Xi-Lin Ge / Xiao-Zhen Wang / Wei Wu / Jun Yan / Guang-Fei Wang / Qing-Tong Zhou / Qiang Liu / Ming-Wei Wang / Zhi-Ping Li /
Abstract: Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents ...Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1-FPR2 in complex with heterotrimeric G to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.
History
DepositionApr 28, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)117,0425
Polymers116,5964
Non-polymers4461
Water00
1


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

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Components

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40110.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04899
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37198.656 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: 5888.812 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
#4: Protein N-formyl peptide receptor 2 / FMLP-related receptor I / FMLP-R-I / Formyl peptide receptor-like 1 / HM63 / Lipoxin A4 receptor / ...FMLP-related receptor I / FMLP-R-I / Formyl peptide receptor-like 1 / HM63 / Lipoxin A4 receptor / LXA4 receptor / RFP


Mass: 33398.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FPR2, FPRH1, FPRL1, LXA4R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25090
#5: Chemical ChemComp-A1L1D / C1R / 4-butoxy-~{N}-[(2~{R})-2-(4-methoxyphenyl)-4-oxidanylidene-1,2-dihydroquinazolin-3-yl]benzamide / Quin C1


Mass: 445.510 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N3O4
Has ligand of interestN
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 formyl peptide receptor 2/C1R receptor in complex with Gi
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (Human) (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: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1309999 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047213
ELECTRON MICROSCOPYf_angle_d0.5659776
ELECTRON MICROSCOPYf_dihedral_angle_d4.813968
ELECTRON MICROSCOPYf_chiral_restr0.0431136
ELECTRON MICROSCOPYf_plane_restr0.0051221

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