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- PDB-7ykd: Cryo-EM structure of the human chemerin receptor 1 complex with t... -

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Entry
Database: PDB / ID: 7ykd
TitleCryo-EM structure of the human chemerin receptor 1 complex with the C-terminal nonapeptide of chemerin
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Chemerin-like receptor 1
  • Retinoic acid receptor responder protein 2
  • scFV16
KeywordsPEPTIDE BINDING PROTEIN / macrophages / inflammation
Function / homology
Function and homology information


adipokinetic hormone binding / adipokinetic hormone receptor activity / platelet dense granule lumen / complement receptor activity / regulation of lipid catabolic process / antifungal innate immune response / chemokine receptor activity / embryonic digestive tract development / Class A/1 (Rhodopsin-like receptors) / antifungal humoral response ...adipokinetic hormone binding / adipokinetic hormone receptor activity / platelet dense granule lumen / complement receptor activity / regulation of lipid catabolic process / antifungal innate immune response / chemokine receptor activity / embryonic digestive tract development / Class A/1 (Rhodopsin-like receptors) / antifungal humoral response / complement receptor mediated signaling pathway / positive regulation of chemotaxis / negative regulation of interleukin-12 production / retinoid metabolic process / negative regulation of NF-kappaB transcription factor activity / positive regulation of macrophage chemotaxis / Adenylate cyclase inhibitory pathway / positive regulation of fat cell differentiation / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of calcium-mediated signaling / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / extracellular matrix / skeletal system development / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / chemotaxis / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / Platelet degranulation / insulin receptor signaling pathway / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / signaling receptor activity / positive regulation of cold-induced thermogenesis / cell cortex / midbody / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / collagen-containing extracellular matrix / defense response to Gram-negative bacterium / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell differentiation / defense response to Gram-positive bacterium / inflammatory response / positive regulation of protein phosphorylation / immune response / G protein-coupled receptor signaling pathway
Similarity search - Function
Retinoic acid receptor responder protein 2 / Chemerin-like receptor 1 / Formyl peptide receptor-related / Cystatin superfamily / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit ...Retinoic acid receptor responder protein 2 / Chemerin-like receptor 1 / Formyl peptide receptor-related / Cystatin superfamily / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
CHOLESTEROL / 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 / Chemerin-like receptor 1 / Retinoic acid receptor responder protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Vicugna pacos (alpaca)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsChen, G. / Liao, Q. / Ye, R.D. / Wang, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Cryo-EM structure of the human chemerin receptor 1-Gi protein complex bound to the C-terminal nonapeptide of chemerin.
Authors: Junlin Wang / Geng Chen / Qiwen Liao / Wenping Lyu / Aijun Liu / Lizhe Zhu / Yang Du / Richard D Ye /
Abstract: Chemerin is a processed protein that acts on G protein-coupled receptors (GPCRs) for its chemotactic and adipokine activities. The biologically active chemerin (chemerin 21-157) results from ...Chemerin is a processed protein that acts on G protein-coupled receptors (GPCRs) for its chemotactic and adipokine activities. The biologically active chemerin (chemerin 21-157) results from proteolytic cleavage of prochemerin and uses its C-terminal peptide containing the sequence YFPGQFAFS for receptor activation. Here we report a high-resolution cryo-electron microscopy (cryo-EM) structure of human chemerin receptor 1 (CMKLR1) bound to the C-terminal nonapeptide of chemokine (C9) in complex with Gi proteins. C9 inserts its C terminus into the binding pocket and is stabilized through hydrophobic interactions involving its Y1, F2, F6, and F8, as well as polar interactions between G4, S9, and several amino acids lining the binding pocket of CMKLR1. Microsecond scale molecular dynamics simulations support a balanced force distribution across the whole ligand-receptor interface that enhances thermodynamic stability of the captured binding pose of C9. The C9 interaction with CMKLR1 is drastically different from chemokine recognition by chemokine receptors, which follow a two-site two-step model. In contrast, C9 takes an "S"-shaped pose in the binding pocket of CMKLR1 much like angiotensin II in the AT1 receptor. Our mutagenesis and functional analyses confirmed the cryo-EM structure and key residues in the binding pocket for these interactions. Our findings provide a structural basis for chemerin recognition by CMKLR1 for the established chemotactic and adipokine activities.
History
DepositionJul 22, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: Retinoic acid receptor responder protein 2
A: Chemerin-like receptor 1
C: 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: scFV16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,12811
Polymers155,1956
Non-polymers1,9335
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area15640 Å2
ΔGint-77 kcal/mol
Surface area46480 Å2

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Components

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

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


Mass: 40153.672 Da / Num. of mol.: 1
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(T) subunit beta-1 / Transducin beta chain 1 / G protein beta subunit


Mass: 37416.930 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 / G protein gamma subunit


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

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Protein/peptide / Protein / Antibody / Non-polymers , 4 types, 8 molecules LAS

#1: Protein/peptide Retinoic acid receptor responder protein 2 / Chemerin / RAR-responsive protein TIG2 / Tazarotene-induced gene 2 protein


Mass: 1063.161 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RARRES2, TIG2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q99969
#2: Protein Chemerin-like receptor 1 / Chemokine-like receptor 1 / G-protein coupled receptor ChemR23 / G-protein coupled receptor DEZ


Mass: 42362.848 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CMKLR1, CHEMR23, DEZ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q99788
#6: Antibody scFV16


Mass: 26337.307 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: a single-chain variable fragment (scFv16) derived from a developed antibody that bind to the αN helix of Gαi subunit used to stabilize the GPCR-G protein complex (https://doi. ...Details: a single-chain variable fragment (scFv16) derived from a developed antibody that bind to the αN helix of Gαi subunit used to stabilize the GPCR-G protein complex (https://doi.org/10.1038/s41467-018-06002-w)
Source: (gene. exp.) Vicugna pacos (alpaca) / Production host: Spodoptera frugiperda (fall armyworm)
#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION

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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

Component
IDNameTypeEntity IDParent-IDSource
1CMKLR1-Gi -scFv16 complexCOMPLEX#1-#60RECOMBINANT
2Retinoic acid receptor responder protein 2COMPLEX#11RECOMBINANT
3Chemerin-like receptor 1, Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#2-#51RECOMBINANT
4scFV16COMPLEX#61RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Vicugna pacos (alpaca)30538
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (E. coli)562
32Spodoptera frugiperda (fall armyworm)7108
43Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding 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: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 1.13 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 432349 / Symmetry type: POINT

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