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- PDB-7t6u: Structure of the human FPR2-Gi complex with CGEN-855A -

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Entry
Database: PDB / ID: 7t6u
TitleStructure of the human FPR2-Gi complex with CGEN-855A
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • B9-scFv
  • N-formyl peptide receptor 2
  • Synthetic peptide
KeywordsSIGNALING PROTEIN / GPCR / membrane protein
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 / complement receptor mediated signaling pathway / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste ...N-formyl peptide receptor activity / complement receptor activity / immune response-regulating cell surface receptor signaling pathway / scavenger receptor binding / complement receptor mediated signaling pathway / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / positive regulation of monocyte chemotaxis / Vasopressin regulates renal water homeostasis via Aquaporins / Formyl peptide receptors bind formyl peptides and many other ligands / positive regulation of innate immune response / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / cargo receptor activity / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / Thrombin signalling through proteinase activated receptors (PARs) / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / photoreceptor outer segment membrane / G alpha (q) signalling events / G alpha (i) signalling events / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / positive chemotaxis / alkylglycerophosphoethanolamine phosphodiesterase activity / tertiary granule membrane / ficolin-1-rich granule membrane / photoreceptor outer segment / specific granule membrane / positive regulation of phagocytosis / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase regulator activity / photoreceptor inner segment / regulation of mitotic spindle organization / cardiac muscle cell apoptotic process / cellular response to forskolin / receptor-mediated endocytosis / positive regulation of superoxide anion generation / astrocyte activation / Regulation of insulin secretion / microglial cell activation / G protein-coupled receptor binding / calcium-mediated signaling / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to peptide hormone / negative regulation of inflammatory response / ADP signalling through P2Y purinoceptor 12 / cellular response to amyloid-beta / Adrenaline,noradrenaline inhibits insulin secretion / chemotaxis / G alpha (z) signalling events / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / GDP binding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling
Similarity search - Function
Formyl peptide receptor-related / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 ...Formyl peptide receptor-related / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
PALMITIC ACID / N-formyl peptide receptor 2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus (rat)
Bos taurus (domestic cattle)
Homo (humans)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsZhuang, Y.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128641 United States
CitationJournal: Nat Commun / Year: 2022
Title: Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2.
Authors: Youwen Zhuang / Lei Wang / Jia Guo / Dapeng Sun / Yue Wang / Weiyi Liu / H Eric Xu / Cheng Zhang /
Abstract: The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally ...The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo-EM structures of G-coupled FPR1 and FPR2 bound to a formylpeptide and G-coupled FPR2 bound to two synthetic peptide and small-molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand-binding pockets to activate FPRs. Our results provide a basis for rational drug design on FPRs.
History
DepositionDec 14, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2022Group: Database references / Structure summary / Category: citation / citation_author / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _struct.title

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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-1
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
E: B9-scFv
L: Synthetic peptide
R: N-formyl peptide receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,9258
Polymers157,4126
Non-polymers5132
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

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


Mass: 40313.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39021.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus (rat) / Gene: Gnb1 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P54311
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7432.554 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P63212

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Antibody / Protein/peptide / Protein / Non-polymers , 4 types, 5 molecules ELR

#4: Antibody B9-scFv


Mass: 26323.324 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus (rat) / Gene: Igh-V7183, Gm16592 / Production host: Spodoptera (butterflies/moths)
#5: Protein/peptide Synthetic peptide


Mass: 1074.275 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo (humans)
#6: 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: 43246.332 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 (butterflies/moths) / References: UniProt: P25090
#7: Chemical ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H32O2

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Details

Has ligand of interestY

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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: formylpeptide receptors FPR2 WITH FMLFII / Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo (humans)9605
31Rattus (rat)10114
41Bos taurus (domestic cattle)9913
Source (recombinant)Organism: Spodoptera (butterflies/moths)
Buffer solutionpH: 7.2
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: 5000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 594109 / Symmetry type: POINT

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