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- PDB-9mi6: Crystal structure of human FcRn in complex with nipocalimab Fab f... -

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Basic information

Entry
Database: PDB / ID: 9mi6
TitleCrystal structure of human FcRn in complex with nipocalimab Fab fragment
Components
  • (nipocalimab Fab ...) x 2
  • Beta-2-microglobulin
  • IgG receptor FcRn large subunit p51
KeywordsIMMUNE SYSTEM / NEONATAL FC RECEPTOR / FCRN / INHIBITOR / BETA 2 MICROGLOBULIN / B2M / COMPLEX(ANTIBODY-ANTIGEN)
Function / homology
Function and homology information


IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor / IgG binding / beta-2-microglobulin binding / : / : / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions ...IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor / IgG binding / beta-2-microglobulin binding / : / : / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions / cellular response to iron ion / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide antigen assembly with MHC class II protein complex / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / MHC class II protein complex / negative regulation of forebrain neuron differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / regulation of iron ion transport / MHC class I peptide loading complex / response to molecule of bacterial origin / HFE-transferrin receptor complex / T cell mediated cytotoxicity / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / antigen processing and presentation of exogenous peptide antigen via MHC class II / MHC class I protein complex / positive regulation of immune response / peptide antigen binding / negative regulation of neurogenesis / positive regulation of T cell mediated cytotoxicity / positive regulation of receptor-mediated endocytosis / multicellular organismal-level iron ion homeostasis / positive regulation of T cell activation / cellular response to nicotine / specific granule lumen / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of cellular senescence / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / negative regulation of epithelial cell proliferation / Interferon gamma signaling / MHC class II protein complex binding / positive regulation of protein binding / Modulation by Mtb of host immune system / late endosome membrane / sensory perception of smell / tertiary granule lumen / DAP12 signaling / negative regulation of neuron projection development / iron ion transport / T cell differentiation in thymus / ER-Phagosome pathway / protein refolding / early endosome membrane / protein homotetramerization / amyloid fibril formation / intracellular iron ion homeostasis / learning or memory / endosome membrane / immune response / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / external side of plasma membrane / lysosomal membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / endoplasmic reticulum / Golgi apparatus / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane / cytosol
Similarity search - Function
Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type ...Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
IgG receptor FcRn large subunit p51 / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å
AuthorsXu, R. / Meador, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mabs / Year: 2025
Title: Nipocalimab, an immunoselective FcRn blocker that lowers IgG and has unique molecular properties.
Authors: Seth, N.P. / Xu, R. / DuPrie, M. / Choudhury, A. / Sihapong, S. / Tyler, S. / Meador, J. / Avery, W. / Cochran, E. / Daly, T. / Brown, J. / Rutitzky, L. / Markowitz, L. / Kumar, S. / ...Authors: Seth, N.P. / Xu, R. / DuPrie, M. / Choudhury, A. / Sihapong, S. / Tyler, S. / Meador, J. / Avery, W. / Cochran, E. / Daly, T. / Brown, J. / Rutitzky, L. / Markowitz, L. / Kumar, S. / Beavers, T. / Bhattacharya, S. / Chen, H. / Parge, V. / Price, K. / Wang, Y. / Sukumaran, S. / Pao, Y. / Abouzahr, K. / Elwood, F. / Duffner, J. / Roy, S. / Narayanaswami, P. / Hubbard, J.J. / Ling, L.E.
History
DepositionDec 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: IgG receptor FcRn large subunit p51
B: Beta-2-microglobulin
H: nipocalimab Fab heavy chain
L: nipocalimab Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,8835
Polymers88,6624
Non-polymers2211
Water4,774265
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)183.282, 67.644, 105.303
Angle α, β, γ (deg.)90.000, 104.879, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-468-

HOH

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein IgG receptor FcRn large subunit p51 / FcRn / IgG Fc fragment receptor transporter alpha chain / Neonatal Fc receptor


Mass: 31236.975 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FCGRT, FCRN / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P55899
#2: Protein Beta-2-microglobulin


Mass: 11748.160 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P61769

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Antibody , 2 types, 2 molecules HL

#3: Antibody nipocalimab Fab heavy chain


Mass: 23082.846 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Generated by papain digestion of nipocalimab IgG / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody nipocalimab Fab light chain


Mass: 22593.857 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Generated by papain digestion of nipocalimab IgG / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars / Non-polymers , 2 types, 266 molecules

#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 265 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.56 Å3/Da / Density % sol: 65.43 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 10% PEG 1000, 10% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 18, 2017
RadiationMonochromator: Si(111) and Si(220) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.41→44.48 Å / Num. obs: 46599 / % possible obs: 95.92 % / Redundancy: 3.2 % / Biso Wilson estimate: 39.95 Å2 / Rmerge(I) obs: 0.144 / Rpim(I) all: 0.095 / Net I/σ(I): 4.78
Reflection shellResolution: 2.41→2.496 Å / Rmerge(I) obs: 0.956 / Mean I/σ(I) obs: 1.02 / Num. unique obs: 4604 / Rpim(I) all: 0.63

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.41→44.48 Å / SU ML: 0.3993 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.6893
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2478 2304 4.96 %
Rwork0.2063 44176 -
obs0.2084 46480 95.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.13 Å2
Refinement stepCycle: LAST / Resolution: 2.41→44.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6058 0 14 265 6337
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00486230
X-RAY DIFFRACTIONf_angle_d0.73638470
X-RAY DIFFRACTIONf_chiral_restr0.0438922
X-RAY DIFFRACTIONf_plane_restr0.00451092
X-RAY DIFFRACTIONf_dihedral_angle_d19.67312231
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.41-2.460.36441530.31742670X-RAY DIFFRACTION94.76
2.46-2.520.36331460.30842716X-RAY DIFFRACTION94.74
2.52-2.580.33241220.30152631X-RAY DIFFRACTION91.22
2.58-2.650.35521430.29312781X-RAY DIFFRACTION97.99
2.65-2.730.33821590.28272776X-RAY DIFFRACTION96.74
2.73-2.820.28851330.25122788X-RAY DIFFRACTION97.43
2.82-2.920.34061420.24952789X-RAY DIFFRACTION96.57
2.92-3.040.30851420.25272726X-RAY DIFFRACTION95.89
3.04-3.170.33151380.25172591X-RAY DIFFRACTION90.45
3.17-3.340.27821450.2432809X-RAY DIFFRACTION97.65
3.34-3.550.27441460.2252831X-RAY DIFFRACTION98.35
3.55-3.820.26261420.19782807X-RAY DIFFRACTION97.62
3.82-4.210.19091430.17472688X-RAY DIFFRACTION92.85
4.21-4.820.16291460.13572896X-RAY DIFFRACTION99.31
4.82-6.070.19781490.1532774X-RAY DIFFRACTION95.77
6.07-44.480.17351550.15952903X-RAY DIFFRACTION97.05
Refinement TLS params.Method: refined / Origin x: 174.303090218 Å / Origin y: 92.3186139992 Å / Origin z: 21.4259562928 Å
111213212223313233
T0.349414875347 Å20.0163678872696 Å2-0.0211054879428 Å2-0.352531872883 Å2-0.01460476159 Å2--0.281369386951 Å2
L0.890352430133 °2-0.0291478502404 °20.516047252222 °2-0.0223857997482 °2-0.0572644735223 °2--0.544986178084 °2
S-0.0162411145449 Å °-0.00011056147186 Å °0.0127203438719 Å °0.00267308320711 Å °0.00970163086172 Å °0.00124939478291 Å °-0.0799120954579 Å °-0.000710335059416 Å °-0.00413706589476 Å °
Refinement TLS groupSelection details: all

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