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PDBsum entry 4zs7
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Immune system
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PDB id
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4zs7
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Contents |
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139 a.a.
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222 a.a.
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210 a.a.
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PDB id:
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| Name: |
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Immune system
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Title:
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Structural mimicry of receptor interaction by antagonistic il-6 antibodies
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Structure:
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Interleukin-6. Chain: a. Fragment: residues 14-184. Synonym: il-6,b-cell stimulatory factor 2,bsf-2,ctl differentiation factor,cdf,hybridoma growth factor,interferon beta-2,ifn-beta-2. Engineered: yes. Llama fab fragment 68f2 heavy chain. Chain: h. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: il6, ifnb2. Expressed in: escherichia coli. Expression_system_taxid: 562. Lama glama. Organism_taxid: 9844. Expressed in: lama glama.
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Resolution:
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2.93Å
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R-factor:
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0.265
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R-free:
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0.293
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Authors:
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C.Blanchetot,N.De Jonge,A.Desmyter,N.Ongenae,E.Hofman,A.Klarenbeek, A.Sadi,A.Hultberg,A.Kretz-Rommel,S.Spinelli,R.Loris,C.Cambillau,H.De Haard
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Key ref:
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C.Blanchetot
et al.
(2016).
Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies.
J Biol Chem,
291,
13846-13854.
PubMed id:
DOI:
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Date:
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13-May-15
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Release date:
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04-May-16
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PROCHECK
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Headers
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References
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P05231
(IL6_HUMAN) -
Interleukin-6 from Homo sapiens
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Seq:
Struc:
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212 a.a.
139 a.a.
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DOI no:
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J Biol Chem
291:13846-13854
(2016)
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PubMed id:
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Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies.
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C.Blanchetot,
N.De Jonge,
A.Desmyter,
N.Ongenae,
E.Hofman,
A.Klarenbeek,
A.Sadi,
A.Hultberg,
A.Kretz-Rommel,
S.Spinelli,
R.Loris,
C.Cambillau,
H.de Haard.
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ABSTRACT
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Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune
diseases and cancer, where it is also involved in metastasis and tissue
invasion. Neutralizing antibodies against IL-6 and its receptor have been
approved for therapeutic intervention or are in advanced stages of clinical
development. Here we describe the crystal structures of the complexes of IL-6
with two Fabs derived from conventional camelid antibodies that antagonize the
interaction between the cytokine and its receptor. The x-ray structures of these
complexes provide insights into the mechanism of neutralization by the two
antibodies and explain the very high potency of one of the antibodies. It
effectively competes for binding to the cytokine with IL-6 receptor (IL-6R) by
using side chains of two CDR residues filling the site I cavities of IL-6, thus
mimicking the interactions of Phe(229) and Phe(279) of IL-6R. In the first
antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe(279)
Mutation of this HCDR3 Trp residue into any other residue except Tyr or Phe
significantly weakens binding of the antibody to IL-6, as was also observed for
IL-6R mutants of Phe(279) In the second antibody, the side chain of HCDR3 valine
ties into site I like IL-6R Phe(279), whereas a LCDR1 tyrosine side chain
occupies a second cavity within site I and mimics the interactions of IL-6R
Phe(229).
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Links
