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- PDB-8iow: Cryo-EM structure of the sarilumab Fab/IL-6R complex -

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Basic information

Entry
Database: PDB / ID: 8iow
TitleCryo-EM structure of the sarilumab Fab/IL-6R complex
Components
  • Heavy chain of Sarilumab Fab
  • Interleukin-6 receptor subunit alpha
  • Light chain of Sarilumab Fab
KeywordsIMMUNE SYSTEM / antibody / IL-6R / structural protein
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 / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type ...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 / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsShe, J. / Chen, L. / Wang, M.X.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Oct 9, 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
Revision 1.3Oct 23, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
I: Interleukin-6 receptor subunit alpha
D2: Interleukin-6 receptor subunit alpha
L: Light chain of Sarilumab Fab
H: Heavy chain of Sarilumab Fab
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,0896
Polymers127,6464
Non-polymers4422
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Interleukin-6 receptor subunit alpha / IL-6 receptor subunit alpha / IL-6R subunit alpha / IL-6R-alpha / IL-6RA / IL-6R 1 / Membrane ...IL-6 receptor subunit alpha / IL-6R subunit alpha / IL-6R-alpha / IL-6RA / IL-6R 1 / Membrane glycoprotein 80 / gp80 / IL-6R-D2


Mass: 40283.441 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6R / Production host: Homo sapiens (human) / References: UniProt: P08887
#2: Antibody Light chain of Sarilumab Fab


Mass: 23253.740 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody Heavy chain of Sarilumab Fab


Mass: 23825.699 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: 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.: 2 / 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
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: the sarilumab Fab/IL-6R complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2700 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134252 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0074282
ELECTRON MICROSCOPYf_angle_d1.0385818
ELECTRON MICROSCOPYf_dihedral_angle_d23.255587
ELECTRON MICROSCOPYf_chiral_restr0.063641
ELECTRON MICROSCOPYf_plane_restr0.009745

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