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- PDB-8k4o: Cryo-EM structure of Kaposi's Sarcoma-Associated Herpesvirus-G Pr... -

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Entry
Database: PDB / ID: 8k4o
TitleCryo-EM structure of Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1
Components
  • G protein-coupled receptor
  • Growth-regulated alpha protein
  • 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 subunit gamma
KeywordsVIRAL PROTEIN / Kaposi's Sarcoma Herpesvirus GPCR / KSHV-GPCR / chemokine
Function / homology
Function and homology information


C-C chemokine binding / C-C chemokine receptor activity / chemokine activity / Chemokine receptors bind chemokines / Interleukin-10 signaling / G protein-coupled serotonin receptor binding / growth factor activity / calcium-mediated signaling / cell chemotaxis / chemotaxis ...C-C chemokine binding / C-C chemokine receptor activity / chemokine activity / Chemokine receptors bind chemokines / Interleukin-10 signaling / G protein-coupled serotonin receptor binding / growth factor activity / calcium-mediated signaling / cell chemotaxis / chemotaxis / specific granule lumen / enzyme activator activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / actin cytoskeleton organization / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / tertiary granule lumen / 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 / nervous system development / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / 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 / GPER1 signaling / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / cell division / extracellular vesicle / positive regulation of cytosolic calcium ion concentration / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / cell cortex / Ca2+ pathway / 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 / Ras protein signal transduction / inflammatory response / Extra-nuclear estrogen signaling / intracellular signal transduction / immune response / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / signaling receptor binding / lysosomal membrane / centrosome / GTPase activity / Neutrophil degranulation / GTP binding / synapse / protein-containing complex binding / signal transduction / metal ion binding / extracellular exosome / extracellular region / membrane / nucleus / plasma membrane / cytosol
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 / 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 / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / G-protein, beta subunit / 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 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 speciesHuman gammaherpesvirus 8
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsLiu, Y.Z. / Liu, A.J.
Funding support1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Dec 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: G protein-coupled receptor
F: Growth-regulated alpha protein
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I) subunit alpha-1
G: Guanine nucleotide-binding protein subunit gamma


Theoretical massNumber of molelcules
Total (without water)127,4825
Polymers127,4825
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein G protein-coupled receptor


Mass: 37881.773 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human gammaherpesvirus 8 / Gene: ORF74 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q76SF8
#2: Protein Growth-regulated alpha protein / C-X-C motif chemokine 1 / GRO-alpha(1-73) / Melanoma growth stimulatory activity / MGSA / ...C-X-C motif chemokine 1 / GRO-alpha(1-73) / Melanoma growth stimulatory activity / MGSA / Neutrophil-activating protein 3 / NAP-3


Mass: 6727.939 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCL1, GRO, GRO1, GROA, MGSA, SCYB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P09341
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 36956.383 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
#4: Protein Guanine nucleotide-binding protein G(I) subunit alpha-1


Mass: 39914.406 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: A0A6P3VR35
#5: Protein Guanine nucleotide-binding protein subunit gamma


Mass: 6001.970 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: A0A663LQV7
Has protein modificationY

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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: Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor (KSHV-GPCR)in complex with CXC chemokine CXCL1 and Gi protein
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD
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: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 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: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107180 / Symmetry type: POINT

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