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- PDB-8u4s: Structure of trimeric CXCR4 in complex with REGN7663 Fab -

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Basic information

Entry
Database: PDB / ID: 8u4s
TitleStructure of trimeric CXCR4 in complex with REGN7663 Fab
Components
  • C-X-C chemokine receptor type 4
  • REGN7663 Fab heavy chain
  • REGN7663 Fab light chain
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / chemokine receptor / trimer / oligomer / antibody / SIGNALING PROTEIN-IMMUNE SYSTEM complex
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 / positive regulation of mesenchymal stem cell migration / neuron recognition / response to ultrasound / telencephalon cell migration / C-X-C chemokine receptor activity / response to tacrolimus ...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 / positive regulation of mesenchymal stem cell migration / neuron recognition / response to ultrasound / telencephalon cell migration / C-X-C chemokine receptor activity / response to tacrolimus / Specification of primordial germ cells / CXCL12-activated CXCR4 signaling pathway / myosin light chain binding / myelin maintenance / positive regulation of vasculature development / regulation of programmed cell death / endothelial tube morphogenesis / C-C chemokine receptor activity / endothelial cell differentiation / Signaling by ROBO receptors / regulation of chemotaxis / : / C-C chemokine binding / positive regulation of dendrite extension / positive regulation of chemotaxis / Formation of definitive endoderm / Chemokine receptors bind chemokines / anchoring junction / dendritic cell chemotaxis / positive regulation of oligodendrocyte differentiation / small molecule binding / epithelial cell development / cell leading edge / cellular response to cytokine stimulus / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / detection of mechanical stimulus involved in sensory perception of pain / Binding and entry of HIV virion / regulation of cell adhesion / coreceptor activity / cardiac muscle contraction / neurogenesis / cell chemotaxis / ubiquitin binding / response to activity / G protein-coupled receptor activity / calcium-mediated signaling / neuron migration / brain development / response to virus / late endosome / cellular response to xenobiotic stimulus / positive regulation of cold-induced thermogenesis / virus receptor activity / actin binding / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / cytoplasmic vesicle / lysosome / early endosome / response to hypoxia / positive regulation of cell migration / inflammatory response / immune response / G protein-coupled receptor signaling pathway / external side of plasma membrane / ubiquitin protein ligase binding / apoptotic process / 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
CHOLESTEROL / Chem-D21 / C-X-C chemokine receptor type 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsSaotome, K. / McGoldrick, L.L. / Franklin, M.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
Citation
Journal: Nat Struct Mol Biol / Year: 2024
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, L.L. / Ho, J. / Ramlall, T. / Shah, S. / Moore, M.J. / Kim, J.H. / Leidich, R. / Olson, W.C. / Franklin, M.C.
History
DepositionSep 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: REGN7663 Fab light chain
H: REGN7663 Fab heavy chain
R: C-X-C chemokine receptor type 4
A: REGN7663 Fab light chain
B: REGN7663 Fab heavy chain
C: C-X-C chemokine receptor type 4
E: REGN7663 Fab light chain
F: REGN7663 Fab heavy chain
G: C-X-C chemokine receptor type 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)367,49318
Polymers363,1489
Non-polymers4,3459
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "L"
d_3ens_1chain "E"
d_1ens_2chain "B"
d_2ens_2chain "F"
d_3ens_2chain "H"
d_1ens_3chain "R"
d_2ens_3chain "C"
d_3ens_3chain "G"
d_1ens_4chain "I"
d_2ens_4chain "D"
d_3ens_4chain "S"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1ASPASPGLUGLUAD1 - 1101 - 110
d_21ens_1ASPASPGLUGLULA1 - 1101 - 110
d_31ens_1ASPASPGLUGLUEG1 - 1101 - 110
d_11ens_2GLNGLNSERSERBE1 - 1251 - 125
d_21ens_2GLNGLNSERSERFH1 - 1251 - 125
d_31ens_2GLNGLNSERSERHB1 - 1251 - 125
d_11ens_3METMETALAALARC24 - 30742 - 325
d_21ens_3METMETALAALACF24 - 30742 - 325
d_31ens_3METMETALAALAGI24 - 30742 - 325
d_11ens_4CLRCLRCLRCLRGP701
d_12ens_4D21D21D21D21GQ702
d_13ens_4CLRCLRCLRCLRGR703
d_21ens_4CLRCLRCLRCLRCM701
d_22ens_4D21D21D21D21CN702
d_23ens_4CLRCLRCLRCLRCO703
d_31ens_4CLRCLRCLRCLRRJ701
d_32ens_4D21D21D21D21RK702
d_33ens_4CLRCLRCLRCLRRL703

NCS ensembles :
ID
ens_1
ens_2
ens_3
ens_4

NCS oper:
IDCodeMatrixVector
1given(-0.500089681729, 0.865973602086, 0.000175264603467), (-0.865973567085, -0.500089570399, -0.000450208686369), (-0.000302220837572, -0.000376919232526, 0.999999883297)96.9829166625, 362.093706187, 0.103103272211
2given(-0.50001311276, -0.866017811069, -0.000194880693062), (0.866017818651, -0.500013132777, 6.94959491658E-5), (-0.000157627635631, -0.000134021266836, 0.999999978596)362.046244244, 96.9928596336, 0.0428190976875
3given(-0.499980592175, -0.866036608606, -1.30420589439E-6), (0.866036608606, -0.499980592171, -2.49411027824E-6), (1.50791317146E-6, -2.37649678356E-6, 0.999999999996)362.010952705, 96.9976118942, 0.000168654782442
4given(-0.500009042613, 0.866020182962, 2.96677084403E-6), (-0.866020182965, -0.500009042602, -3.65804599418E-6), (-1.68452941182E-6, -4.39833950455E-6, 0.999999999989)96.9953230518, 362.006224322, 0.000861279220715
5given(-0.499941074014, -0.866059421945, 1.3166984467E-5), (0.866059421138, -0.499941072737, 5.33798795106E-5), (-3.96474312533E-5, 3.8090185239E-5, 0.999999998489)361.996294815, 96.9813843579, 0.00140634832134
6given(-0.500016054886, 0.866016134169, -1.46629753903E-5), (-0.866016134256, -0.50001605495, -7.90976257987E-7), (-8.01672130966E-6, 1.23028724362E-5, 0.999999999892)97.0088530706, 362.004761832, -0.000659179507153
7given(-0.499979232109, 0.866037393799, -1.36448674204E-6), (-0.866037393754, -0.499979232098, -9.50492968973E-6), (-8.91383957023E-6, -3.57057090563E-6, 0.999999999954)96.9951964301, 362.01242944, 0.00191007670875
8given(-0.500013242132, -0.866017758276, -6.57978733793E-6), (0.866017758213, -0.500013242175, 1.04595299199E-5), (-1.23481194535E-5, -4.68309213488E-7, 0.999999999924)362.007468477, 96.9965991324, 0.00198357614096

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Components

#1: Antibody REGN7663 Fab light chain


Mass: 24185.904 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody REGN7663 Fab heavy chain


Mass: 25799.934 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein C-X-C chemokine receptor type 4


Mass: 71063.609 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CXCR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P61073
#4: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H46O
#5: Chemical ChemComp-D21 / (2R)-1-(hexadecanoyloxy)-3-(phosphonooxy)propan-2-yl (9Z)-octadec-9-enoate


Mass: 674.929 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C37H71O8P
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: Trimeric CXCR4 in complex with REGN7663 Fab / Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
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: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 27104 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 69.89 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003513023
ELECTRON MICROSCOPYf_angle_d0.715217709
ELECTRON MICROSCOPYf_chiral_restr0.04461992
ELECTRON MICROSCOPYf_plane_restr0.00582157
ELECTRON MICROSCOPYf_dihedral_angle_d5.94321845
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2DAELECTRON MICROSCOPYNCS constraints0.000710231672969
ens_1d_3DAELECTRON MICROSCOPYNCS constraints0.000715037713169
ens_2d_2EBELECTRON MICROSCOPYNCS constraints0.000593379449044
ens_2d_3EBELECTRON MICROSCOPYNCS constraints0.000591637054661
ens_3d_2CRELECTRON MICROSCOPYNCS constraints0.000702744915074
ens_3d_3CRELECTRON MICROSCOPYNCS constraints0.000681654568856
ens_4d_2PGELECTRON MICROSCOPYNCS constraints0.0005471622343
ens_4d_3PGELECTRON MICROSCOPYNCS constraints0.000583472940313

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