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- PDB-7wvx: Cryo-EM structure of the human formyl peptide receptor 2 in compl... -

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Basic information

Entry
Database: PDB / ID: 7wvx
TitleCryo-EM structure of the human formyl peptide receptor 2 in complex with fhumanin and Gi2
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
  • Humanin
  • Soluble cytochrome b562,N-formyl peptide receptor 2
KeywordsSIGNALING PROTEIN / G protein-coupled receptor / formyl peptide receptor / FPR2 / humanin
Function / homology
Function and homology information


negative regulation of interleukin-18 production / N-formyl peptide receptor activity / complement receptor activity / dentinogenesis / immune response-regulating cell surface receptor signaling pathway / receptor antagonist activity / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of neuroinflammatory response / scavenger receptor binding / negative regulation of NLRP3 inflammasome complex assembly ...negative regulation of interleukin-18 production / N-formyl peptide receptor activity / complement receptor activity / dentinogenesis / immune response-regulating cell surface receptor signaling pathway / receptor antagonist activity / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of neuroinflammatory response / scavenger receptor binding / negative regulation of NLRP3 inflammasome complex assembly / negative regulation of calcium ion-dependent exocytosis / negative regulation of interleukin-1 production / RAGE receptor binding / negative regulation of adenylate cyclase activity / negative regulation of execution phase of apoptosis / G protein-coupled adenosine receptor signaling pathway / negative regulation of amyloid fibril formation / positive regulation of innate immune response / complement receptor mediated signaling pathway / positive regulation of neural precursor cell proliferation / positive regulation of monocyte chemotaxis / negative regulation of synaptic transmission / Formyl peptide receptors bind formyl peptides and many other ligands / leukocyte chemotaxis / positive regulation of urine volume / negative regulation of response to oxidative stress / cargo receptor activity / gamma-aminobutyric acid signaling pathway / positive chemotaxis / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / tertiary granule membrane / ficolin-1-rich granule membrane / positive regulation of vascular associated smooth muscle cell proliferation / neuronal dense core vesicle / sperm flagellum / specific granule membrane / positive regulation of superoxide anion generation / response to nutrient / supramolecular fiber organization / Adenylate cyclase inhibitory pathway / astrocyte activation / positive regulation of phagocytosis / receptor-mediated endocytosis / sperm midpiece / hippocampal mossy fiber to CA3 synapse / calcium-mediated signaling / mitochondrion organization / electron transport chain / Regulation of insulin secretion / negative regulation of inflammatory response / microglial cell activation / G protein-coupled receptor binding / chemotaxis / cellular response to amyloid-beta / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / phospholipase C-activating 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 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / cell-cell signaling / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / negative regulation of neuron apoptotic process / amyloid-beta binding / GPER1 signaling / positive regulation of cytosolic calcium ion concentration / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / angiogenesis / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs)
Similarity search - Function
Humanin family / Humanin family / Formyl peptide receptor-related / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H ...Humanin family / Humanin family / Formyl peptide receptor-related / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / Mainly Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-2 / Soluble cytochrome b562 / 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 / Humanin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsZhu, Y. / Lin, X. / Zong, X. / Han, S. / Zhao, Q. / Wu, B.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31730027 China
National Natural Science Foundation of China (NSFC)31825010 China
National Natural Science Foundation of China (NSFC)82121005 China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of FPR2 in recognition of Aβ and neuroprotection by humanin.
Authors: Ya Zhu / Xiaowen Lin / Xin Zong / Shuo Han / Mu Wang / Yuxuan Su / Limin Ma / Xiaojing Chu / Cuiying Yi / Qiang Zhao / Beili Wu /
Abstract: Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ and serves as a receptor for humanin, a peptide that protects neuronal cells from damage ...Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Aβ, implying its involvement in the pathogenesis of Alzheimer's disease (AD). However, the interaction pattern between FPR2 and Aβ or humanin remains unknown. Here we report the structures of FPR2 bound to G and Aβ or N-formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Aβ and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.
History
DepositionFeb 11, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 13, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Humanin
R: Soluble cytochrome b562,N-formyl peptide receptor 2
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


Theoretical massNumber of molelcules
Total (without water)146,5385
Polymers146,5385
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide Humanin / Humanin mitochondrial / HNM


Mass: 2719.275 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q8IVG9
#2: Protein Soluble cytochrome b562,N-formyl peptide receptor 2 / Cytochrome b-562 / FMLP-related receptor I / FMLP-R-I / Formyl peptide receptor-like 1 / HM63 / ...Cytochrome b-562 / FMLP-related receptor I / FMLP-R-I / Formyl peptide receptor-like 1 / HM63 / Lipoxin A4 receptor / LXA4 receptor / RFP


Mass: 56710.328 Da / Num. of mol.: 1 / Mutation: S211L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: cybC, FPR2, FPRH1, FPRL1, LXA4R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: P25090
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40502.863 Da / Num. of mol.: 1 / Mutation: S47N, G204A, A327S, E246A
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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 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
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 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
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: Formyl peptide receptor 2 in complex with fhumanin and Gi2
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
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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 2.1875 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.18.2_3874refinement
PHENIX1.18.2_3874refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1398841 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 52.75 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00187218
ELECTRON MICROSCOPYf_angle_d0.46789799
ELECTRON MICROSCOPYf_chiral_restr0.03951154
ELECTRON MICROSCOPYf_plane_restr0.00371223
ELECTRON MICROSCOPYf_dihedral_angle_d3.5744975

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