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- EMDB-60348: Cryo-EM strucutre of CXCR4 complexed with antagonist HF51116 -

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Basic information

Entry
Database: EMDB / ID: EMD-60348
TitleCryo-EM strucutre of CXCR4 complexed with antagonist HF51116
Map data
Sample
  • Complex: HF51116-CXCR4-KOR-Nb6
    • Protein or peptide: Nb6 nanobody
    • Protein or peptide: Soluble cytochrome b562,C-X-C chemokine receptor type 4
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-N-[[4-[[3-(cyclohexylamino)propylamino]methyl]phenyl]methyl]-5-(diaminomethylideneamino)-2-(pyridin-2-ylmethylamino)pentanamide
KeywordsCXC motif chemokine receptor 4 / antagonist / SIGNALING PROTEIN
Function / homology
Function and homology information


C-X-C motif chemokine 12 receptor activity / regulation of viral process / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / neuron recognition / telencephalon cell migration / positive regulation of mesenchymal stem cell migration / response to tacrolimus / response to ultrasound / Specification of primordial germ cells ...C-X-C motif chemokine 12 receptor activity / regulation of viral process / positive regulation of vascular wound healing / positive regulation of macrophage migration inhibitory factor signaling pathway / neuron recognition / telencephalon cell migration / positive regulation of mesenchymal stem cell migration / response to tacrolimus / response to ultrasound / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / C-X-C chemokine receptor activity / regulation of programmed cell death / positive regulation of vasculature development / endothelial tube morphogenesis / endothelial cell differentiation / Signaling by ROBO receptors / regulation of chemotaxis / positive regulation of dendrite extension / Formation of definitive endoderm / C-C chemokine receptor activity / positive regulation of chemotaxis / C-C chemokine binding / Developmental Lineage of Pancreatic Acinar Cells / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / epithelial cell development / cellular response to cytokine stimulus / small molecule binding / cell leading edge / detection of temperature stimulus involved in sensory perception of pain / positive regulation of oligodendrocyte differentiation / regulation of calcium ion transport / Binding and entry of HIV virion / detection of mechanical stimulus involved in sensory perception of pain / regulation of cell adhesion / coreceptor activity / cardiac muscle contraction / neurogenesis / ubiquitin binding / response to activity / cell chemotaxis / calcium-mediated signaling / electron transport chain / G protein-coupled receptor activity / brain development / response to virus / neuron migration / late endosome / cellular response to xenobiotic stimulus / actin binding / positive regulation of cold-induced thermogenesis / virus receptor activity / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / G alpha (i) signalling events / periplasmic space / early endosome / electron transfer activity / response to hypoxia / lysosome / immune response / positive regulation of cell migration / G protein-coupled receptor signaling pathway / inflammatory response / iron ion binding / external side of plasma membrane / apoptotic process / heme binding / 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 / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / Chemokine receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
Soluble cytochrome b562 / C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsJiao HZ / Hu HL
Funding support China, 1 items
OrganizationGrant numberCountry
Other government32100963 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Structural mechanisms underlying the modulation of CXCR4 by diverse small-molecule antagonists.
Authors: Xiaohong Sang / Haizhan Jiao / Qian Meng / Xiong Fang / Qi Pan / Jiao Zhou / Tingli Qian / Wanqin Zhang / Yan Xu / Jing An / Ziwei Huang / Hongli Hu /
Abstract: CXCR4 (CXC chemokine receptor type 4), a member of the G protein-coupled receptor superfamily, plays a role in cell migration and functions as a coreceptor for HIV entry. Molecular therapeutics ...CXCR4 (CXC chemokine receptor type 4), a member of the G protein-coupled receptor superfamily, plays a role in cell migration and functions as a coreceptor for HIV entry. Molecular therapeutics targeting CXCR4 have been under intensive investigation. To date, only two small-molecule antagonist drugs targeting CXCR4, plerixafor (AMD3100) and mavorixafor (AMD070), have been approved. Here, we present the high-resolution structures of CXCR4 complexed with AMD3100 and AMD070, as well as a small-molecule antagonist HF51116 that has very different chemical structure and binding mechanism from AMD3100 and AMD070. The interactions between these antagonists and the receptor are analyzed in details, and the mechanisms of antagonism are elucidated. Both the major and minor subpockets on CXCR4 are found to be involved in binding of these small-molecule antagonists. The distinct conformations of Trp94 observed in these structures highlight the plasticity of the binding pocket on CXCR4, offering valuable insights into the exploration and refinement of therapeutic strategies targeting this chemokine receptor.
History
DepositionMay 30, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateApr 2, 2025-
Current statusApr 2, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60348.png

Downloads & links

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Map

FileDownload / File: emd_60348.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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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
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.047157507 - 0.074229516
Average (Standard dev.)-0.00000094784167 (±0.0012159739)
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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Additional map: unsharpened map

Fileemd_60348_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_60348_half_map_1.map
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60348_half_map_2.map
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Sample components

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Entire : HF51116-CXCR4-KOR-Nb6

EntireName: HF51116-CXCR4-KOR-Nb6
Components
  • Complex: HF51116-CXCR4-KOR-Nb6
    • Protein or peptide: Nb6 nanobody
    • Protein or peptide: Soluble cytochrome b562,C-X-C chemokine receptor type 4
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-N-[[4-[[3-(cyclohexylamino)propylamino]methyl]phenyl]methyl]-5-(diaminomethylideneamino)-2-(pyridin-2-ylmethylamino)pentanamide

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Supramolecule #1: HF51116-CXCR4-KOR-Nb6

SupramoleculeName: HF51116-CXCR4-KOR-Nb6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Nb6 nanobody

MacromoleculeName: Nb6 nanobody / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 18.665906 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAMA QVQLQESGGG LVQAGESLRL SCAASGTIFR LYDMGWYRRV SGNQRELVA SITSGGSTKY GDSVKGRFTI SRDNAKNTVY LQMSSLKPED TAVYYCNAEY RTGIWEELLD GWGQGTQVTV S SHHHHHHH H

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Macromolecule #2: Soluble cytochrome b562,C-X-C chemokine receptor type 4

MacromoleculeName: Soluble cytochrome b562,C-X-C chemokine receptor type 4
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.451062 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKGSADLE DNWETLNDNL KVIEKADNAA QVKDALTKMR AAALDAQKAT PPKLEDKSPD SPEMKDFRH GFDILVGQID DALKLANEGK VKEAQAAAEQ LKTTRNAYIQ KYLLVPRGSM EGISIYTSDN YTEEMGSGDY D SMKEPCFR ...String:
MKTIIALSYI FCLVFADYKD DDDKGSADLE DNWETLNDNL KVIEKADNAA QVKDALTKMR AAALDAQKAT PPKLEDKSPD SPEMKDFRH GFDILVGQID DALKLANEGK VKEAQAAAEQ LKTTRNAYIQ KYLLVPRGSM EGISIYTSDN YTEEMGSGDY D SMKEPCFR EENANFNKIF LPTIYSIIFL TGIVGNGLVI LVMGYQKKLR SMTDKYRLHL SVADLLFVIT LPFWAVDAVA NW YFGNFLC KAVHVIYTVN LYSSVWILAF ISLDRYLAIV HATNSQRPRK LLAEKVVYVG VWIPALLLTI PDFIFANVSE ADD RYICDR FYPNDLWVVV FQFQHIMVGL ILPGIVILSC YCIIISRLKS VRLLSGSREK DRNLRRITRP TVILILAFFA CWLP YYIGI SIDSFILLEI IKQGCEFENT VHKWISITEA LAFFHCCLNP ILYAFLGAKF KTSAQHALTS GRPLEVLFQG PHHHH HHHH HH

UniProtKB: Soluble cytochrome b562, C-X-C chemokine receptor type 4, C-X-C chemokine receptor type 4

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: (2S)-N-[[4-[[3-(cyclohexylamino)propylamino]methyl]phenyl]methyl]...

MacromoleculeName: (2S)-N-[[4-[[3-(cyclohexylamino)propylamino]methyl]phenyl]methyl]-5-(diaminomethylideneamino)-2-(pyridin-2-ylmethylamino)pentanamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1D8K
Molecular weightTheoretical: 522.729 Da

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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
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 51.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 142111
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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