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4zs7

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Revision as of 17:34, 12 July 2016

Structural mimicry of receptor interaction by antagonistic IL-6 antibodies

Structural highlights

4zs7 is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[IL6_HUMAN] Genetic variations in IL6 are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302]. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. Note=A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men.

Function

[IL6_HUMAN] Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Involved in lymphocyte and monocyte differentiation. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation Acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance.

Publication Abstract from PubMed

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 Phe229 and Phe279 of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to 'hot spot' residue Phe279. 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 Phe279. In the second antibody, the side-chain of HCDR3 valine ties into site I like IL-6R Phe279, while a LCDR1 tyrosine side-chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe229.

Structural mimicry of receptor interaction by antagonistic IL-6 antibodies.,Blanchetot C, de Jonge N, Desmyter A, Ongenae N, Hofman E, Klarenbeek A, Sadi A, Hultberg A, Kretz-Rommel A, Spinelli S, Loris R, Cambillau C, de Haard H J Biol Chem. 2016 Apr 27. pii: jbc.M115.695528. PMID:27129274^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Blanchetot C, de Jonge N, Desmyter A, Ongenae N, Hofman E, Klarenbeek A, Sadi A, Hultberg A, Kretz-Rommel A, Spinelli S, Loris R, Cambillau C, de Haard H. Structural mimicry of receptor interaction by antagonistic IL-6 antibodies. J Biol Chem. 2016 Apr 27. pii: jbc.M115.695528. PMID:27129274 doi:http://dx.doi.org/10.1074/jbc.M115.695528

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zs7"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4zs7]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZS7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZS7 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zs7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zs7 OCA], [http://pdbe.org/4zs7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zs7 RCSB], [http://www.ebi.ac.uk/pdbsum/4zs7 PDBsum]</span></td></tr>
+</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zs7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zs7 OCA], [http://pdbe.org/4zs7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zs7 RCSB], [http://www.ebi.ac.uk/pdbsum/4zs7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zs7 ProSAT]</span></td></tr>
 </table>
 == Disease ==

4zs7

From Proteopedia

Revision as of 17:34, 12 July 2016

Structural mimicry of receptor interaction by antagonistic IL-6 antibodies

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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