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- EMDB-41893: Structure of trimeric CXCR4 in complex with REGN7663 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-41893
TitleStructure of trimeric CXCR4 in complex with REGN7663 Fab
Map data
Sample
  • Complex: Trimeric CXCR4 in complex with REGN7663 Fab
    • Protein or peptide: REGN7663 Fab light chain
    • Protein or peptide: REGN7663 Fab heavy chain
    • Protein or peptide: C-X-C chemokine receptor type 4
  • Ligand: CHOLESTEROL
  • Ligand: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate
KeywordsGPCR / chemokine receptor / trimer / oligomer / antibody / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / positive regulation of macrophage migration inhibitory factor signaling pathway / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / C-X-C chemokine receptor activity / positive regulation of vasculature development / Signaling by ROBO receptors / regulation of chemotaxis ...C-X-C motif chemokine 12 receptor activity / positive regulation of macrophage migration inhibitory factor signaling pathway / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / C-X-C chemokine receptor activity / positive regulation of vasculature development / Signaling by ROBO receptors / regulation of chemotaxis / Formation of definitive endoderm / C-C chemokine receptor activity / C-C chemokine binding / Developmental Lineage of Pancreatic Acinar Cells / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / cell leading edge / cellular response to cytokine stimulus / positive regulation of oligodendrocyte differentiation / Binding and entry of HIV virion / regulation of cell adhesion / coreceptor activity / neurogenesis / ubiquitin binding / cell chemotaxis / calcium-mediated signaling / G protein-coupled receptor activity / brain development / response to virus / late endosome / positive regulation of cold-induced thermogenesis / actin binding / virus receptor activity / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / G alpha (i) signalling events / response to hypoxia / early endosome / lysosome / immune response / positive regulation of cell migration / G protein-coupled receptor signaling pathway / inflammatory response / external side of plasma membrane / apoptotic process / ubiquitin protein ligase binding / cell surface / protein-containing complex / extracellular exosome / plasma membrane / cytoplasm
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / 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)
Similarity search - Domain/homology
C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsSaotome K / McGoldrick LL / Franklin MC
Funding support United States, 1 items
OrganizationGrant numberCountry
Not funded United States
Citation
Journal: Nat Struct Mol Biol / Year: 2025
Title: Structural insights into CXCR4 modulation and oligomerization.
Authors: Kei Saotome / Luke L McGoldrick / Jo-Hao Ho / Trudy F Ramlall / Sweta Shah / Michael J Moore / Jee Hae Kim / Raymond Leidich / William C Olson / Matthew C Franklin /
Abstract: Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an ...Activation of the chemokine receptor CXCR4 by its chemokine ligand CXCL12 regulates diverse cellular processes. Previously reported crystal structures of CXCR4 revealed the architecture of an inactive, homodimeric receptor. However, many structural aspects of CXCR4 remain poorly understood. Here, we use cryo-electron microscopy to investigate various modes of human CXCR4 regulation. CXCL12 activates CXCR4 by inserting its N terminus deep into the CXCR4 orthosteric pocket. The binding of US Food and Drug Administration-approved antagonist AMD3100 is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle. A potent antibody blocker, REGN7663, binds across the extracellular face of CXCR4 and inserts its complementarity-determining region H3 loop into the orthosteric pocket. Trimeric and tetrameric structures of CXCR4 reveal modes of G-protein-coupled receptor oligomerization. We show that CXCR4 adopts distinct subunit conformations in trimeric and tetrameric assemblies, highlighting how oligomerization could allosterically regulate chemokine receptor function.
#1: Journal: Biorxiv / Year: 2024
Title: Structural insights into CXCR4 modulation and oligomerization
Authors: Saotome K / McGoldrick LL / Ho J / Ramlall T / Shah S / Moore MJ / Kim JH / Leidich R / Olson WC / Franklin MC
History
DepositionSep 11, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41893.png

Downloads & links

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Map

FileDownload / File: emd_41893.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 360 pix.
= 306. Å		0.85 Å/pix.
x 360 pix.
= 306. Å		0.85 Å/pix.
x 360 pix.
= 306. Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.6474834 - 0.9745147
Average (Standard dev.)-0.00017338677 (±0.028682148)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 306.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41893_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41893_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Trimeric CXCR4 in complex with REGN7663 Fab

EntireName: Trimeric CXCR4 in complex with REGN7663 Fab
Components
  • Complex: Trimeric CXCR4 in complex with REGN7663 Fab
    • Protein or peptide: REGN7663 Fab light chain
    • Protein or peptide: REGN7663 Fab heavy chain
    • Protein or peptide: C-X-C chemokine receptor type 4
  • Ligand: CHOLESTEROL
  • Ligand: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate

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Supramolecule #1: Trimeric CXCR4 in complex with REGN7663 Fab

SupramoleculeName: Trimeric CXCR4 in complex with REGN7663 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: REGN7663 Fab light chain

MacromoleculeName: REGN7663 Fab light chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.185904 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DVVMTQSPLS LPVTLGQPAS ISCRSSQSLV YTDGNTYLNW FQQRPGQSPR RLIYKVSNRD SGVPDRFSGS GSGTDFTLKI SRVEAEDVG FYYCMQNTHW PLTFGGGTKV EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA KVQWKVDNAL Q SGNSQESV ...String:
DVVMTQSPLS LPVTLGQPAS ISCRSSQSLV YTDGNTYLNW FQQRPGQSPR RLIYKVSNRD SGVPDRFSGS GSGTDFTLKI SRVEAEDVG FYYCMQNTHW PLTFGGGTKV EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA KVQWKVDNAL Q SGNSQESV TEQDSKDSTY SLSSTLTLSK ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE C

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Macromolecule #2: REGN7663 Fab heavy chain

MacromoleculeName: REGN7663 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.799934 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGIEWMGW ISTYNGNRNY AQKVQGRVTM TTDRSTSTAY MDLRSLRSD DTAVYYCARH GITGARNYYY HYGMDVWGQG TTVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF P EPVTVSWN ...String:
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYGISWVRQA PGQGIEWMGW ISTYNGNRNY AQKVQGRVTM TTDRSTSTAY MDLRSLRSD DTAVYYCARH GITGARNYYY HYGMDVWGQG TTVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF P EPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT CNVDHKPSNT KVDKRVESKY GPPCPPCPAP PV

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Macromolecule #3: C-X-C chemokine receptor type 4

MacromoleculeName: C-X-C chemokine receptor type 4 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.063609 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFAGAPE GISIYTSDNY TEEMGSGDYD SMKEPCFREE NANFNKIFLP TIYSIIFLTG IVGNGLVILV MGYQKKLRS MTDKYRLHLS VADLLFVITL PFWAVDAVAN WYFGNFLCKA VHVIYTVSLY SSVLILAFIS LDRYLAIVHA T NSQRPRKL ...String:
MKTIIALSYI FCLVFAGAPE GISIYTSDNY TEEMGSGDYD SMKEPCFREE NANFNKIFLP TIYSIIFLTG IVGNGLVILV MGYQKKLRS MTDKYRLHLS VADLLFVITL PFWAVDAVAN WYFGNFLCKA VHVIYTVSLY SSVLILAFIS LDRYLAIVHA T NSQRPRKL LAEKVVYVGV WIPALLLTIP DFIFANVSEA DDRYICDRFY PNDLWVVVFQ FQHIMVGLIL PGIVILSCYC II ISKLSHS KGHQKRKALK TTVILILAFF ACWLPYYIGI SIDSFILLEI IKQGCEFENT VHKWISITEA LAFFHCCLNP ILY AFLGAK FKTSAQHALT SVSRGSSLKI LSKGKRGGHS SVSTESESSS FHSSGRPLEV LFQGPGGGGS VSKGEELFTG VVPI LVELD GDVNGHKFSV SGEGEGDATY GKLTLKFICT TGKLPVPWPT LVTTLTYGVQ CFSRYPDHMK QHDFFKSAMP EGYVQ ERTI FFKDDGNYKT RAEVKFEGDT LVNRIELKGI DFKEDGNILG HKLEYNYNSH NVYIMADKQK NGIKVNFKIR HNIEDG SVQ LADHYQQNTP IGDGPVLLPD NHYLSTQSKL SKDPNEKRDH MVLLEFVTAA GITLGMDELY KDYKDDDDK

UniProtKB: C-X-C chemokine receptor type 4

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 6 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec...

MacromoleculeName: (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate
type: ligand / ID: 5 / Number of copies: 3 / Formula: D21
Molecular weightTheoretical: 674.929 Da
Chemical component information

ChemComp-D21:
(2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate

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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

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 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: NONE
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 27104
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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