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- EMDB-36888: Cryo-EM structure of Kaposi's Sarcoma-Associated Herpesvirus-G Pr... -

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Entry
Database: EMDB / ID: EMD-36888
TitleCryo-EM structure of Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1
Map data
Sample
  • Complex: Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1 and Gi protein
    • Protein or peptide: G protein-coupled receptor
    • Protein or peptide: Growth-regulated alpha protein
    • 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) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein subunit gamma
KeywordsKaposi's Sarcoma Herpesvirus GPCR / KSHV-GPCR / chemokine / VIRAL PROTEIN
Function / homology
Function and homology information


C-C chemokine receptor activity / C-C chemokine binding / chemokine activity / Chemokine receptors bind chemokines / Interleukin-10 signaling / G protein-coupled serotonin receptor binding / enzyme activator activity / cell chemotaxis / growth factor activity / calcium-mediated signaling ...C-C chemokine receptor activity / C-C chemokine binding / chemokine activity / Chemokine receptors bind chemokines / Interleukin-10 signaling / G protein-coupled serotonin receptor binding / enzyme activator activity / cell chemotaxis / growth factor activity / calcium-mediated signaling / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / specific granule lumen / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / chemotaxis / photoreceptor disc membrane / Glucagon-type ligand receptors / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / tertiary granule lumen / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / nervous system development / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / actin cytoskeleton organization / GTPase binding / positive regulation of cytosolic calcium ion concentration / Ca2+ pathway / retina development in camera-type eye / 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 / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / intracellular signal transduction / immune response / G protein-coupled receptor signaling pathway / inflammatory response / signaling receptor binding / lysosomal membrane / negative regulation of cell population proliferation / cell division / GTPase activity / synapse / centrosome / Neutrophil degranulation / protein-containing complex binding / GTP binding / signal transduction / extracellular space / extracellular exosome / extracellular region / metal ion binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
CXC chemokine / CXC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-x-C subfamily signature. / CXC Chemokine domain / : / Chemokine beta/gamma/delta / Intercrine alpha family (small cytokine C-X-C) (chemokine CXC). / Chemokine interleukin-8-like domain / Chemokine interleukin-8-like superfamily / Small cytokines (intecrine/chemokine), interleukin-8 like ...CXC chemokine / CXC chemokine, conserved site / Small cytokines (intercrine/chemokine) C-x-C subfamily signature. / CXC Chemokine domain / : / Chemokine beta/gamma/delta / Intercrine alpha family (small cytokine C-X-C) (chemokine CXC). / Chemokine interleukin-8-like domain / Chemokine interleukin-8-like superfamily / Small cytokines (intecrine/chemokine), interleukin-8 like / G-protein alpha subunit, group I / 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 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 / 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 subunit gamma / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Growth-regulated alpha protein / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / G protein-coupled receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / Human gammaherpesvirus 8
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsLiu YZ / Liu AJ
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition.
Authors: Aijun Liu / Yezhou Liu / Clàudia Llinàs Del Torrent Masachs / Weijia Zhang / Leonardo Pardo / Richard D Ye /
Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi's sarcoma. KSHV-GPCR shares a ...Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi's sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. Like other herpesvirus-encoded GPCRs, KSHV-GPCR is characterized by its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent and constitutive activation of KSHV-GPCR, obtaining high-resolution cryo-EM structures of KSHV-GPCR-Gi complexes with and without the bound CXCL1 chemokine. Analysis of the apo-KSHV-GPCR-Gi structure (2.81 Å) unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. In comparison, the CXCL1-bound KSHV-GPCR-Gi structure (3.01 Å) showed a two-site binding mode and provided detailed information of CXCL1 binding to a chemokine receptor. The dual activation mechanism employed by KSHV-GPCR represents an evolutionary adaptation for immune evasion and contributes to the pathogenesis of Kaposi's sarcoma. Together with results from functional assays that confirmed the structural models, these findings may help to develop therapeutic strategies for KSHV infection.
History
DepositionJul 20, 2023-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateDec 11, 2024-
Current statusDec 11, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36888.png

Downloads & links

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Map

FileDownload / File: emd_36888.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-2.4423473 - 4.1872015
Average (Standard dev.)-0.0019661942 (±0.09202834)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36888_half_map_1.map
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Half map: #2

Fileemd_36888_half_map_2.map
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Sample components

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Entire : Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Recepto...

EntireName: Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1 and Gi protein
Components
  • Complex: Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1 and Gi protein
    • Protein or peptide: G protein-coupled receptor
    • Protein or peptide: Growth-regulated alpha protein
    • 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) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein subunit gamma

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Supramolecule #1: Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Recepto...

SupramoleculeName: Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1 and Gi protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: G protein-coupled receptor

MacromoleculeName: G protein-coupled receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human gammaherpesvirus 8
Molecular weightTheoretical: 37.881773 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DFLTIFLDDD ESWNETLNMS GYDYSGNFSL EVSVCEMTTV VPYTWNVGIL SLIFLINVLG NGLVTYIFCK HRSRAGAIDI LLLGICLNS LCLSISLLAE VLMFLFPNII STGLCRLEIF FYYLYVYLDI FSVVCVSLVR YLLVAYSTRS WPKKQSLGWV L TSAALLIA ...String:
DFLTIFLDDD ESWNETLNMS GYDYSGNFSL EVSVCEMTTV VPYTWNVGIL SLIFLINVLG NGLVTYIFCK HRSRAGAIDI LLLGICLNS LCLSISLLAE VLMFLFPNII STGLCRLEIF FYYLYVYLDI FSVVCVSLVR YLLVAYSTRS WPKKQSLGWV L TSAALLIA LVLSGDACRH RSRVVDPVSK QAMCYENAGN MTADWRLHVR TVSVTAGFLL PLALLILFYA LTWCVVRRTK LQ ARRKVRG VIVAVVLLFF VFCFPYHVLN LLDTLLRRRW IRDSCYTRGL INVGLAVTSL LQALYSAVVP LIYSCLGSLF RQR MYGLFQ SLRQSFM

UniProtKB: G protein-coupled receptor

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Macromolecule #2: Growth-regulated alpha protein

MacromoleculeName: Growth-regulated alpha protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.727939 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
ASVATELRCQ CLQTLQGIHP KNIQSVNVKS PGPHCAQTEV IATLKNGRKA CLNPASPIVK KII

UniProtKB: Growth-regulated alpha protein

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Macromolecule #3: 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: 3 / 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 #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: 39.914406 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: LSAEDKAAVE RSKMIDRNLR EDGEKAAREV KLLLLGAGES GKSTIVKQMK IIHEAGYSEE ECKQYKAVVY SNTIQSIIAI IRAMGRLKI DFGDAARADD ARQLFVLAGS AEEGFMTAEL AGVIKRLWKD GGVQACFSRS REYQLNDSAA YYLNDLDRIS Q GSYIPTQQ ...String:
LSAEDKAAVE RSKMIDRNLR EDGEKAAREV KLLLLGAGES GKSTIVKQMK IIHEAGYSEE ECKQYKAVVY SNTIQSIIAI IRAMGRLKI DFGDAARADD ARQLFVLAGS AEEGFMTAEL AGVIKRLWKD GGVQACFSRS REYQLNDSAA YYLNDLDRIS Q GSYIPTQQ DVLRTRVKTT GIVETHFTFK DLHFKMFDVG GQRSERKKWI HCFEGVTAII FCVALSDYDL VLAEDEEMNR MH ESMKLFD SICNNKWFTD TSIILFLNKK DLFEEKIKKS PLTICYPEYA GSNTYEEAAA YIQCQFEDLN KRKDTKEIYT HFT CATDTK NVQFVFDAVT DVIIKNNLKD CGLF

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

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Macromolecule #5: Guanine nucleotide-binding protein subunit gamma

MacromoleculeName: Guanine nucleotide-binding protein subunit gamma / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.00197 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
IAQARKLVEQ LKMEANIDRI KVSKAAADLM AYCEAHAKED PLLTPVPASE NPFR

UniProtKB: Guanine nucleotide-binding protein subunit gamma

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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: 7.4
GridMaterial: GOLD
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: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6lfo

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 107180
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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