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- PDB-8zpl: Cryo-EM strucutre of CXCR4 complexed with antagonist HF51116 -

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Basic information

Entry
Database: PDB / ID: 8zpl
TitleCryo-EM strucutre of CXCR4 complexed with antagonist HF51116
Components
  • Nb6 nanobody
  • Soluble cytochrome b562,C-X-C chemokine receptor type 4
KeywordsSIGNALING PROTEIN / CXC motif chemokine receptor 4 / antagonist
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 / positive regulation of chemotaxis / C-C chemokine receptor activity / C-C chemokine binding / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / epithelial cell development / cellular response to cytokine stimulus / cell leading edge / small molecule binding / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / positive regulation of oligodendrocyte differentiation / Binding and entry of HIV virion / regulation of cell adhesion / detection of mechanical stimulus involved in sensory perception of pain / coreceptor activity / cardiac muscle contraction / ubiquitin binding / response to activity / neurogenesis / cell chemotaxis / calcium-mediated signaling / neuron migration / electron transport chain / G protein-coupled receptor activity / brain development / response to virus / late endosome / cellular response to xenobiotic stimulus / 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 / lysosome / early endosome / electron transfer activity / response to hypoxia / periplasmic space / positive regulation of cell migration / immune response / 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
: / CHOLESTEROL / Soluble cytochrome b562 / C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesLama glama (llama)
Escherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsJiao, H.Z. / Hu, H.L.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Apr 2, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
N: Nb6 nanobody
R: Soluble cytochrome b562,C-X-C chemokine receptor type 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,4135
Polymers74,1172
Non-polymers1,2963
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: Antibody Nb6 nanobody


Mass: 18665.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Protein Soluble cytochrome b562,C-X-C chemokine receptor type 4 / Cytochrome b-562 / CXC-R4 / CXCR-4 / FB22 / Fusin / HM89 / LCR1 / Leukocyte-derived seven ...Cytochrome b-562 / CXC-R4 / CXCR-4 / FB22 / Fusin / HM89 / LCR1 / Leukocyte-derived seven transmembrane domain receptor / LESTR / Lipopolysaccharide-associated protein 3 / LAP-3 / LPS-associated protein 3 / NPYRL / Stromal cell-derived factor 1 receptor / SDF-1 receptor


Mass: 55451.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, CXCR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: P61073
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical ChemComp-A1D8K / (2S)-N-[[4-[[3-(cyclohexylamino)propylamino]methyl]phenyl]methyl]-5-(diaminomethylideneamino)-2-(pyridin-2-ylmethylamino)pentanamide / HF51116


Mass: 522.729 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H46N8O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: HF51116-CXCR4-KOR-Nb6 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
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: 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: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 51.6 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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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: 142111 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033319
ELECTRON MICROSCOPYf_angle_d0.5234526
ELECTRON MICROSCOPYf_dihedral_angle_d7.034492
ELECTRON MICROSCOPYf_chiral_restr0.04524
ELECTRON MICROSCOPYf_plane_restr0.004544

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