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- EMDB-40450: Cryo-EM structure of CMKLR1 signaling complex -

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Entry
Database: EMDB / ID: EMD-40450
TitleCryo-EM structure of CMKLR1 signaling complex
Map dataCMKLR1 complex map
Sample
  • Complex: Chemerin9-CMKLR1-Gi complex
    • Protein or peptide: Chemerin-like receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Chemerin 9
    • Protein or peptide: scFv16
  • Ligand: CHOLESTEROL
  • Ligand: PALMITIC ACID
KeywordsGPCR / Peptide agonist / Chemerin9 / Membrane protein / SIGNALING PROTEIN
Function / homology
Function and homology information


adipokinetic hormone binding / adipokinetic hormone receptor activity / complement receptor activity / chemokine receptor activity / Class A/1 (Rhodopsin-like receptors) / complement receptor mediated signaling pathway / negative regulation of interleukin-12 production / positive regulation of macrophage chemotaxis / negative regulation of NF-kappaB transcription factor activity / Adenylate cyclase inhibitory pathway ...adipokinetic hormone binding / adipokinetic hormone receptor activity / complement receptor activity / chemokine receptor activity / Class A/1 (Rhodopsin-like receptors) / complement receptor mediated signaling pathway / negative regulation of interleukin-12 production / positive regulation of macrophage chemotaxis / negative regulation of NF-kappaB transcription factor activity / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / positive regulation of fat cell differentiation / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / regulation of calcium-mediated signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / skeletal system development / 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 / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / chemotaxis / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / signaling receptor activity / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / immune response / cell cycle / inflammatory response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane
Similarity search - Function
Chemerin-like receptor 1 / Formyl peptide receptor-related / 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. ...Chemerin-like receptor 1 / Formyl peptide receptor-related / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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 / Chemerin-like receptor 1
Similarity search - Component
Biological speciesSpodoptera frugiperda (fall armyworm) / Homo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsZhang X / Zhang C
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128641 United States
CitationJournal: PLoS Biol / Year: 2023
Title: Structural basis of G protein-Coupled receptor CMKLR1 activation and signaling induced by a chemerin-derived agonist.
Authors: Xuan Zhang / Tina Weiß / Mary Hongying Cheng / Siqi Chen / Carla Katharina Ambrosius / Anne Sophie Czerniak / Kunpeng Li / Mingye Feng / Ivet Bahar / Annette G Beck-Sickinger / Cheng Zhang /
Abstract: Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin ...Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both pro- and anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist-induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation.
History
DepositionApr 11, 2023-
Header (metadata) releaseNov 1, 2023-
Map releaseNov 1, 2023-
UpdateDec 20, 2023-
Current statusDec 20, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40450.png

Downloads & links

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Map

FileDownload / File: emd_40450.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCMKLR1 complex map
Voxel sizeX=Y=Z: 0.848 Å
Density
Contour LevelBy AUTHOR: 0.148
Minimum - Maximum-1.009961 - 1.457571
Average (Standard dev.)0.0006021041 (±0.041298848)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.088 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: CMKLR1 complex map half A

Fileemd_40450_half_map_1.map
AnnotationCMKLR1 complex map half_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CMKLR1 complex map half B

Fileemd_40450_half_map_2.map
AnnotationCMKLR1 complex map half_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Chemerin9-CMKLR1-Gi complex

EntireName: Chemerin9-CMKLR1-Gi complex
Components
  • Complex: Chemerin9-CMKLR1-Gi complex
    • Protein or peptide: Chemerin-like receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Chemerin 9
    • Protein or peptide: scFv16
  • Ligand: CHOLESTEROL
  • Ligand: PALMITIC ACID

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Supramolecule #1: Chemerin9-CMKLR1-Gi complex

SupramoleculeName: Chemerin9-CMKLR1-Gi complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)

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Macromolecule #1: Chemerin-like receptor 1

MacromoleculeName: Chemerin-like receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.079715 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: ARVTRIFLVV VYSIVCFLGI LGNGLVIIIA TFKMKKTVNM VWFLNLAVAD FLFNVFLPIH ITYAAMDYHW VFGTAMCKIS NFLLIHNMF TSVFLLTIIS SDRCISVLLP VWSQNHRSVR LAYMACMVIW VLAFFLSSPS LVFRDTANLH GKISCFNNFS L STPGSSSW ...String:
ARVTRIFLVV VYSIVCFLGI LGNGLVIIIA TFKMKKTVNM VWFLNLAVAD FLFNVFLPIH ITYAAMDYHW VFGTAMCKIS NFLLIHNMF TSVFLLTIIS SDRCISVLLP VWSQNHRSVR LAYMACMVIW VLAFFLSSPS LVFRDTANLH GKISCFNNFS L STPGSSSW PTHSQMDPVG YSRHMVVTVT RFLCGFLVPV LIITACYLTI VCKLQRNRLA KTKKPFKIIV TIIITFFLCW CP YHTLNLL ELHHTAMPGS VFSLGLPLAT ALAIANSCMN PILYVFMGQD FKKFK

UniProtKB: Chemerin-like receptor 1

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.956383 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSAS QDGKLIIWDS YTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT GYLSCCRFLD DNQIVTSSGD T TCALWDIE ...String:
DQLRQEAEQL KNQIRDARKA CADATLSQIT NNIDPVGRIQ MRTRRTLRGH LAKIYAMHWG TDSRLLVSAS QDGKLIIWDS YTTNKVHAI PLRSSWVMTC AYAPSGNYVA CGGLDNICSI YNLKTREGNV RVSRELAGHT GYLSCCRFLD DNQIVTSSGD T TCALWDIE TGQQTTTFTG HTGDVMSLSL APDTRLFVSG ACDASAKLWD VREGMCRQTF TGHESDINAI CFFPNGNAFA TG SDDATCR LFDLRADQEL MTYSHDNIIC GITSVSFSKS GRLLLAGYDD FNCNVWDALK ADRAGVLAGH DNRVSCLGVT DDG MAVATG SWDSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
IAQARKLVQQ LKMEANIDRI KVSKAAADLM AYCEAHAKED PLLTPVPASQ NPFR

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.12266 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TLSAEDKAAV ERSKMIDRNL REDGEKAARE VKLLLLGAGE SGKNTIVKQM KIIHEAGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ ...String:
TLSAEDKAAV ERSKMIDRNL REDGEKAARE VKLLLLGAGE SGKNTIVKQM KIIHEAGYSE EECKQYKAVV YSNTIQSIIA IIRAMGRLK IDFGDSARAD DARQLFVLAG AAEEGFMTAE LAGVIKRLWK DSGVQACFNR SREYQLNDSA AYYLNDLDRI A QPNYIPTQ QDVLRTRVKT TGIVETHFTF KDLHFKMFDV GAQRSERKKW IHCFEGVTAI IFCVALSDYD LVLAEDEEMN RM HASMKLF DSICNNKWFT DTSIILFLNK KDLFEEKIKK SPLTICYPEY AGSNTYEEAA AYIQCQFEDL NKRKDTKEIY THF TCSTDT KNVQFVFDAV TDVIIKNNLK DCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #5: Chemerin 9

MacromoleculeName: Chemerin 9 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.063161 KDa
SequenceString:
YFPGQFAFS

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Macromolecule #6: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 28.634797 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL LEENLYFQGA SHHHHHHHH

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #8: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 8 / Number of copies: 2 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 56.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 242745

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