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- PDB-9upv: Cryo-EM structure of CXCR4 complexed with agonist SDVX1 -

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Entry
Database: PDB / ID: 9upv
TitleCryo-EM structure of CXCR4 complexed with agonist SDVX1
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,C-X-C chemokine receptor type 4,Oplophorus-luciferin 2-monooxygenase catalytic subunit
  • Stromal cell-derived factor 1
  • single-chain variable fragment scFv16
KeywordsSIGNALING PROTEIN / CXC motif chemokine receptor 4 / agonist
Function / homology
Function and homology information


Oplophorus-luciferin 2-monooxygenase / Oplophorus-luciferin 2-monooxygenase activity / telencephalon cell migration / chemokine (C-X-C motif) ligand 12 signaling pathway / C-X-C motif chemokine 12 receptor activity / response to ultrasound / negative regulation of leukocyte tethering or rolling / regulation of actin polymerization or depolymerization / positive regulation of macrophage migration inhibitory factor signaling pathway / myosin light chain binding ...Oplophorus-luciferin 2-monooxygenase / Oplophorus-luciferin 2-monooxygenase activity / telencephalon cell migration / chemokine (C-X-C motif) ligand 12 signaling pathway / C-X-C motif chemokine 12 receptor activity / response to ultrasound / negative regulation of leukocyte tethering or rolling / regulation of actin polymerization or depolymerization / positive regulation of macrophage migration inhibitory factor signaling pathway / myosin light chain binding / CXCL12-activated CXCR4 signaling pathway / Specification of primordial germ cells / chemokine receptor binding / myelin maintenance / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / CXCR chemokine receptor binding / C-X-C chemokine receptor activity / positive regulation of axon extension involved in axon guidance / positive regulation of vasculature development / Signaling by ROBO receptors / induction of positive chemotaxis / negative regulation of dendritic cell apoptotic process / Formation of definitive endoderm / integrin activation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of dopamine secretion / cellular response to chemokine / C-C chemokine receptor activity / C-C chemokine binding / positive regulation of monocyte chemotaxis / anchoring junction / chemokine activity / Chemokine receptors bind chemokines / dendritic cell chemotaxis / blood circulation / positive regulation of calcium ion import / cellular response to cytokine stimulus / cell leading edge / detection of temperature stimulus involved in sensory perception of pain / positive regulation of oligodendrocyte differentiation / animal organ regeneration / Binding and entry of HIV virion / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of T cell migration / Nuclear signaling by ERBB4 / regulation of cell adhesion / coreceptor activity / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / positive regulation of endothelial cell proliferation / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / positive regulation of neuron differentiation / D2 dopamine receptor binding / neurogenesis / positive regulation of cell adhesion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / axon guidance / cellular response to forskolin / bioluminescence / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / growth factor activity / cell chemotaxis / adult locomotory behavior / ubiquitin binding / Regulation of insulin secretion / calcium-mediated signaling / neuropeptide signaling pathway / defense response / response to prostaglandin E / electron transport chain / brain development / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / integrin binding / response to peptide hormone / G protein-coupled receptor activity / neuron migration / chemotaxis / response to virus / centriolar satellite / G-protein beta/gamma-subunit complex binding / intracellular calcium ion homeostasis / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / 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 / Prostacyclin signalling through prostacyclin receptor
Similarity search - Function
CXC chemokine receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CXC Chemokine domain / Chemokine receptor family / 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 receptor 4 N-terminal domain / CXCR4 Chemokine receptor N terminal / CXC chemokine receptor 4/atypical chemokine receptor 2 / CXC Chemokine domain / Chemokine receptor family / 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 / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Calycin / 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 / 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
CHOLESTEROL / Soluble cytochrome b562 / Stromal cell-derived factor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / C-X-C chemokine receptor type 4 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Oplophorus-luciferin 2-monooxygenase catalytic subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
Oplophorus gracilirostris (arthropod)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsJiao, H.Z. / Sang, X.H. / Huang, Z.W. / Hu, H.L.
Funding support China, 1items
OrganizationGrant numberCountry
Other government32100963 China
CitationJournal: bioRxiv / Year: 2025
Title: The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS.
Authors: Xiaohong Sang / Haizhan Jiao / Qian Meng / Xiong Fang / Kartik S Sundaram / Jiao Zhou / Yan Xu / Asuka I W Alvarado / Ruslan L Nuryyev / Jitka Ourenik / Vaclav Ourednik / Iris S Huang / ...Authors: Xiaohong Sang / Haizhan Jiao / Qian Meng / Xiong Fang / Kartik S Sundaram / Jiao Zhou / Yan Xu / Asuka I W Alvarado / Ruslan L Nuryyev / Jitka Ourenik / Vaclav Ourednik / Iris S Huang / Xiang Liu / Yuheng Mei / Tingli Qian / Aaron Ciechanover / Donald P Pizzo / Michael A Lane / Lyandysha V Zholudeva / Jing An / Evan Y Snyder / Hongli Hu / Ziwei Huang /
Abstract: G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor ...G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1α. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1α in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1α that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1 mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases.
History
DepositionApr 29, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 29, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
J: Stromal cell-derived factor 1
R: Soluble cytochrome b562,C-X-C chemokine receptor type 4,Oplophorus-luciferin 2-monooxygenase catalytic subunit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
S: single-chain variable fragment scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)192,1247
Polymers191,7386
Non-polymers3871
Water00
1


  • Idetical with deposited unit
  • defined by author
  • 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 BCA

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 42005.895 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
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 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
#5: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40445.059 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: P63096

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Protein/peptide / Protein / Antibody / Non-polymers , 4 types, 4 molecules JRS

#3: Protein/peptide Stromal cell-derived factor 1 / SDF-1 / hSDF-1 / C-X-C motif chemokine 12 / Intercrine reduced in hepatomas / IRH / hIRH / Pre-B ...SDF-1 / hSDF-1 / C-X-C motif chemokine 12 / Intercrine reduced in hepatomas / IRH / hIRH / Pre-B cell growth-stimulating factor / PBSF


Mass: 951.122 Da / Num. of mol.: 1 / Fragment: N-terminus / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P48061
#4: Protein Soluble cytochrome b562,C-X-C chemokine receptor type 4,Oplophorus-luciferin 2-monooxygenase catalytic subunit / 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 / 19kOLase


Mass: 72689.641 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. exp.) Oplophorus gracilirostris (arthropod)
Gene: cybC, CXCR4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0ABE7, UniProt: P61073, UniProt: Q9GV45, Oplophorus-luciferin 2-monooxygenase
#6: Antibody single-chain variable fragment scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestN
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: SDVX1-CXCR4-DNGi-scFv16 / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 55.2 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 194772 / Symmetry type: POINT
RefinementHighest resolution: 2.7 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029032
ELECTRON MICROSCOPYf_angle_d0.4212252
ELECTRON MICROSCOPYf_dihedral_angle_d3.6611228
ELECTRON MICROSCOPYf_chiral_restr0.0391401
ELECTRON MICROSCOPYf_plane_restr0.0031534

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