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- EMDB-35627: Cryo-EM structure of the sarilumab Fab/IL-6R complex -

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Basic information

Entry
Database: EMDB / ID: EMD-35627
TitleCryo-EM structure of the sarilumab Fab/IL-6R complex
Map data
Sample
  • Complex: the sarilumab Fab/IL-6R complex
    • Protein or peptide: Interleukin-6 receptor subunit alpha
    • Protein or peptide: Light chain of Sarilumab Fab
    • Protein or peptide: Heavy chain of Sarilumab Fab
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsantibody / IL-6R / structural protein / IMMUNE SYSTEM
Function / homology
Function and homology information


ciliary neurotrophic factor binding / interleukin-6 receptor activity / interleukin-6 binding / hepatic immune response / : / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor-mediated signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-6 receptor complex ...ciliary neurotrophic factor binding / interleukin-6 receptor activity / interleukin-6 binding / hepatic immune response / : / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor-mediated signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-6 receptor complex / negative regulation of collagen biosynthetic process / endocrine pancreas development / T-helper 17 cell lineage commitment / negative regulation of interleukin-8 production / positive regulation of glomerular mesangial cell proliferation / vascular endothelial growth factor production / positive regulation of leukocyte chemotaxis / neutrophil mediated immunity / cytokine receptor activity / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / monocyte chemotaxis / MAPK1 (ERK2) activation / positive regulation of osteoblast differentiation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of chemokine production / extrinsic apoptotic signaling pathway / response to cytokine / acute-phase response / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / positive regulation of interleukin-6 production / Transcriptional regulation of granulopoiesis / positive regulation of peptidyl-tyrosine phosphorylation / Interleukin-4 and Interleukin-13 signaling / defense response to Gram-negative bacterium / Potential therapeutics for SARS / positive regulation of MAPK cascade / receptor complex / defense response to Gram-positive bacterium / apical plasma membrane / external side of plasma membrane / positive regulation of cell population proliferation / enzyme binding / protein homodimerization activity / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / : / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type 3 domain ...Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / : / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-6 receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsShe J / Chen L / Wang MX
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2021YFF0600800 China
CitationJournal: Cell Rep / Year: 2024
Title: Structural insights into IL-6 signaling inhibition by therapeutic antibodies.
Authors: Mingxing Wang / Long Chen / Jin He / Wenqiang Xia / Zihong Ye / Ji She /
Abstract: Antibody inhibitors of the interleukin-6 (IL-6) signaling pathway, such as tocilizumab and sarilumab, have been used to treat rheumatoid arthritis, chimeric antigen receptor T cell-induced cytokine ...Antibody inhibitors of the interleukin-6 (IL-6) signaling pathway, such as tocilizumab and sarilumab, have been used to treat rheumatoid arthritis, chimeric antigen receptor T cell-induced cytokine storm, and severe COVID-19 pneumonia. Here, we solve the cryogenic electron microscopy structures of sarilumab and tocilizumab in complex with IL-6R to resolutions of 3.2 and 3.3 Å, respectively. These structures reveal that both tocilizumab and sarilumab bind to the D3 domain of IL-6R. The binding surfaces of the two antibodies largely overlap, but the detailed interactions are different. Functional studies of various mutants show results consistent with our structural analysis of the antibodies and IL-6R interactions. Structural comparisons with the IL-6/IL-6R/gp130 complex indicate that sarilumab and tocilizumab probably inhibit IL-6/IL-6R signaling by competing for the IL-6 binding site. In summary, this work reveals the antibody-blocking mechanism of the IL-6 signaling pathway and paves the way for future antibody discovery.
History
DepositionMar 13, 2023-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_35627.png

Downloads & links

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Map

FileDownload / File: emd_35627.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 384 pix.
= 314.88 Å		0.82 Å/pix.
x 384 pix.
= 314.88 Å		0.82 Å/pix.
x 384 pix.
= 314.88 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-1.1115209 - 1.7207795
Average (Standard dev.)-0.0001873702 (±0.020389501)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 314.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35627_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_35627_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : the sarilumab Fab/IL-6R complex

EntireName: the sarilumab Fab/IL-6R complex
Components
  • Complex: the sarilumab Fab/IL-6R complex
    • Protein or peptide: Interleukin-6 receptor subunit alpha
    • Protein or peptide: Light chain of Sarilumab Fab
    • Protein or peptide: Heavy chain of Sarilumab Fab
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: the sarilumab Fab/IL-6R complex

SupramoleculeName: the sarilumab Fab/IL-6R complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Interleukin-6 receptor subunit alpha

MacromoleculeName: Interleukin-6 receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.283441 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLAVGCALLA ALLAAPGAAL APRRCPAQEV ARGVLTSLPG DSVTLTCPGV EPEDNATVHW VLRKPAAGSH PSRWAGMGRR LLLRSVQLH DSGNYSCYRA GRPAGTVHLL VDVPPEEPQL SCFRKSPLSN VVCEWGPRST PSLTTKAVLL VRKFQNSPAE D FQEPCQYS ...String:
MLAVGCALLA ALLAAPGAAL APRRCPAQEV ARGVLTSLPG DSVTLTCPGV EPEDNATVHW VLRKPAAGSH PSRWAGMGRR LLLRSVQLH DSGNYSCYRA GRPAGTVHLL VDVPPEEPQL SCFRKSPLSN VVCEWGPRST PSLTTKAVLL VRKFQNSPAE D FQEPCQYS QESQKFSCQL AVPEGDSSFY IVSMCVASSV GSKFSKTQTF QGCGILQPDP PANITVTAVA RNPRWLSVTW QD PHSWNSS FYRLRFELRY RAERSKTFTT WMVKDLQHHC VIHDAWSGLR HVVQLRAQEE FGQGEWSEWS PEAMGTPWTE SRS PPAENE VSTPMQALTT NKDDDNILFR DSANATSLPG SRRRGSCGL

UniProtKB: Interleukin-6 receptor subunit alpha

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Macromolecule #2: Light chain of Sarilumab Fab

MacromoleculeName: Light chain of Sarilumab Fab / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.25374 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS VSASVGDRVT ITCRASQGIS SWLAWYQQKP GKAPKLLIYG ASSLESGVPS RFSGSGSGTD FTLTISSLQP EDFASYYCQ QANSFPYTFG QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS VSASVGDRVT ITCRASQGIS SWLAWYQQKP GKAPKLLIYG ASSLESGVPS RFSGSGSGTD FTLTISSLQP EDFASYYCQ QANSFPYTFG QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: Heavy chain of Sarilumab Fab

MacromoleculeName: Heavy chain of Sarilumab Fab / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.825699 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVQPGRSLRL SCAASRFTFD DYAMHWVRQA PGKGLEWVSG ISWNSGRIGY ADSVKGRFTI SRDNAENSLF LQMNGLRAE DTALYYCAKG RDSFDIWGQG TMVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS G ALTSGVHT ...String:
EVQLVESGGG LVQPGRSLRL SCAASRFTFD DYAMHWVRQA PGKGLEWVSG ISWNSGRIGY ADSVKGRFTI SRDNAENSLF LQMNGLRAE DTALYYCAKG RDSFDIWGQG TMVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS G ALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEPKS CDKTH

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.4000000000000001 µm

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 134252
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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