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

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Basic information

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 / negative regulation of interleukin-12 production / Class A/1 (Rhodopsin-like receptors) / complement receptor mediated signaling pathway / positive regulation of macrophage chemotaxis / skeletal system development / regulation of calcium-mediated signaling ...adipokinetic hormone binding / adipokinetic hormone receptor activity / complement receptor activity / chemokine receptor activity / negative regulation of interleukin-12 production / Class A/1 (Rhodopsin-like receptors) / complement receptor mediated signaling pathway / positive regulation of macrophage chemotaxis / skeletal system development / regulation of calcium-mediated signaling / positive regulation of fat cell differentiation / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / neuropeptide signaling pathway / Regulation of insulin secretion / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / chemotaxis / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating 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) / GDP binding / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / 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 / positive regulation of cold-induced thermogenesis / 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 / extracellular vesicle / regulation of inflammatory response / Thrombin signalling through proteinase activated receptors (PARs) / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / signaling receptor activity / ciliary basal body / GTPase binding / midbody / G protein activity / Ca2+ pathway / cell cortex / 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 / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / Extra-nuclear estrogen signaling / immune response / inflammatory response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / centrosome / GTPase activity / synapse
Similarity search - Function
Chemerin-like receptor 1 / Formyl peptide receptor-related / G-protein alpha subunit, group I / 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. ...Chemerin-like receptor 1 / Formyl peptide receptor-related / G-protein alpha subunit, group I / 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
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-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing 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
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.088 Å		0.85 Å/pix.
x 256 pix.
= 217.088 Å		0.85 Å/pix.
x 256 pix.
= 217.088 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.848 Å
Density

Histogram

Histogram (log scale)
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

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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

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

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Image processing

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

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