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- PDB-9ast: Cryo-EM structure of XCR1 signaling complex -

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Basic information

Entry
Database: PDB / ID: 9ast
TitleCryo-EM structure of XCR1 signaling complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Chemokine XC receptor 1,Non structural polyprotein
  • Lymphotactin
  • scFv16
KeywordsSIGNALING PROTEIN / GPCR / XCL1 / Membrane protein
Function / homology
Function and homology information


mature natural killer cell chemotaxis / positive regulation of granzyme A production / negative regulation of T-helper 1 cell activation / positive regulation of immunoglobulin production in mucosal tissue / positive regulation of granzyme B production / positive regulation of thymocyte migration / positive regulation of B cell chemotaxis / negative regulation of T-helper 1 type immune response / negative regulation of T cell cytokine production / positive regulation of transforming growth factor beta production ...mature natural killer cell chemotaxis / positive regulation of granzyme A production / negative regulation of T-helper 1 cell activation / positive regulation of immunoglobulin production in mucosal tissue / positive regulation of granzyme B production / positive regulation of thymocyte migration / positive regulation of B cell chemotaxis / negative regulation of T-helper 1 type immune response / negative regulation of T cell cytokine production / positive regulation of transforming growth factor beta production / positive regulation of natural killer cell chemotaxis / chemokine receptor binding / positive regulation of T cell chemotaxis / positive regulation of T-helper 1 cell cytokine production / chemokine receptor activity / CCR chemokine receptor binding / positive regulation of T-helper 2 cell cytokine production / positive regulation of leukocyte chemotaxis / negative regulation of CD4-positive, alpha-beta T cell proliferation / C-C chemokine receptor activity / chemokine-mediated signaling pathway / positive regulation of CD4-positive, alpha-beta T cell proliferation / C-C chemokine binding / chemokine activity / positive regulation of neutrophil chemotaxis / Chemokine receptors bind chemokines / positive regulation of CD8-positive, alpha-beta T cell proliferation / negative regulation of interleukin-2 production / negative regulation of type II interferon production / positive regulation of interleukin-10 production / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / cellular response to transforming growth factor beta stimulus / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / neutrophil chemotaxis / release of sequestered calcium ion into cytosol / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to interleukin-4 / cellular response to forskolin / positive regulation of release of sequestered calcium ion into cytosol / regulation of mitotic spindle organization / cell chemotaxis / Regulation of insulin secretion / calcium-mediated signaling / positive regulation of cholesterol biosynthetic process / positive regulation of T cell cytokine production / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of T cell mediated cytotoxicity / response to virus / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / chemotaxis / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / 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 / antimicrobial humoral immune response mediated by antimicrobial peptide / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / GDP binding / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cell-cell signaling / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / extracellular vesicle
Similarity search - Function
XC chemokine receptor 1 / C chemokine / : / 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 / Calycin / G-protein alpha subunit, group I ...XC chemokine receptor 1 / C chemokine / : / 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 / Calycin / 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 / 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
Non structural polyprotein / Chemokine XC receptor 1 / Lymphotactin / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsZhang, X. / Zhang, C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128641 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Molecular basis for chemokine recognition and activation of XCR1.
Authors: Xuan Zhang / Roman R Schlimgen / Stephanie Singh / Michael P Tomani / Brian F Volkman / Cheng Zhang /
Abstract: The X-C motif chemokine receptor XCR1, which selectively binds to the chemokine XCL1, is highly expressed in conventional dendritic cells subtype 1 (cDC1s) and crucial for their activation. ...The X-C motif chemokine receptor XCR1, which selectively binds to the chemokine XCL1, is highly expressed in conventional dendritic cells subtype 1 (cDC1s) and crucial for their activation. Modulating XCR1 signaling in cDC1s could offer novel opportunities in cancer immunotherapy and vaccine development by enhancing the antigen presentation function of cDC1s. To investigate the molecular mechanism of XCL-induced XCR1 signaling, we determined a high-resolution structure of the human XCR1 and G complex with an engineered form of XCL1, XCL1 CC3, by cryoelectron microscopy. Through mutagenesis and structural analysis, we elucidated the molecular details for the binding of the N-terminal segment of XCL1 CC3, which is vital for activating XCR1. The unique arrangement within the XCL1 CC3 binding site confers specificity for XCL1 in XCR1. We propose an activation mechanism for XCR1 involving structural alterations of key residues at the bottom of the XCL1 binding pocket. These detailed insights into XCL1 CC3-XCR1 interaction and XCR1 activation pave the way for developing novel XCR1-targeted therapeutics.
History
DepositionFeb 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
L: Lymphotactin
R: Chemokine XC receptor 1,Non structural polyprotein
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
E: scFv16


Theoretical massNumber of molelcules
Total (without water)189,9416
Polymers189,9416
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

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


Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, A326S
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


Mass: 38744.371 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


Mass: 7859.173 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 , 2 types, 2 molecules LR

#2: Protein Lymphotactin / ATAC / C motif chemokine 1 / Cytokine SCM-1 / Lymphotaxin / SCM-1-alpha / Small-inducible cytokine ...ATAC / C motif chemokine 1 / Cytokine SCM-1 / Lymphotaxin / SCM-1-alpha / Small-inducible cytokine C1 / XC chemokine ligand 1


Mass: 13905.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XCL1, LTN, SCYC1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P47992
#3: Protein Chemokine XC receptor 1,Non structural polyprotein / G-protein coupled receptor 5 / Lymphotactin receptor / XC chemokine receptor 1


Mass: 60383.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XCR1, CCXCR1, GPR5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P46094, UniProt: A0A482LYE4

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Antibody , 1 types, 1 molecules E

#6: Antibody scFv16


Mass: 28634.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Details

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: XCL1-XCR1-Gi complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Tecnai Spirit / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI SPIRIT
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: 1000 nm
Image recordingElectron dose: 55 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: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 255110 / Symmetry type: POINT

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