5i5k

From Proteopedia

(Difference between revisions)

Revision as of 18:01, 12 July 2016

Structure of complement C5 in complex with eculizumab

Structural highlights

5i5k is a 6 chain structure with sequence from [1] and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CO5_HUMAN] Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:609536]. A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Note=An association study of C5 haplotypes and genotypes in individuals with chronic hepatitis C virus infection shows that individuals homozygous for the C5_1 haplotype have a significantly higher stage of liver fibrosis than individuals carrying at least 1 other allele (PubMed:15995705).

Function

[CO5_HUMAN] Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled. Derived from proteolytic degradation of complement C5, C5 anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. C5a also stimulates the locomotion of polymorphonuclear leukocytes (chemokinesis) and direct their migration toward sites of inflammation (chemotaxis).

Publication Abstract from PubMed

Eculizumab is a humanized mAb approved for treatment of patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab binds complement component C5 and prevents its cleavage by C5 convertases, inhibiting release of both the proinflammatory metabolite C5a and formation of the membrane attack complex via C5b. In this study, we present the crystal structure of the complex between C5 and a Fab fragment with the same sequence as eculizumab at a resolution of 4.2 A. Five CDRs contact the C5 macroglobulin 7 domain, which contains the entire epitope. A complete mutational scan of the 66 CDR residues identified 28 residues as important for the C5-eculizumab interaction, and the structure of the complex offered an explanation for the reduced C5 binding observed for these mutant Abs. Furthermore, the structural observations of the interaction are supported by the reduced ability of a subset of these mutated Abs to inhibit membrane attack complex formation as tested in a hemolysis assay. Our results suggest that eculizumab functions by sterically preventing C5 from binding to convertases and explain the exquisite selectivity of eculizumab for human C5 and how polymorphisms in C5 cause eculizumab-resistance in a small number of patients with paroxysmal nocturnal hemoglobinuria.

Structural Basis for Eculizumab-Mediated Inhibition of the Complement Terminal Pathway.,Schatz-Jakobsen JA, Zhang Y, Johnson K, Neill A, Sheridan D, Andersen GR J Immunol. 2016 Jul 1;197(1):337-44. doi: 10.4049/jimmunol.1600280. Epub 2016 May, 18. PMID:27194791^[1]

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

References

↑ Schatz-Jakobsen JA, Zhang Y, Johnson K, Neill A, Sheridan D, Andersen GR. Structural Basis for Eculizumab-Mediated Inhibition of the Complement Terminal Pathway. J Immunol. 2016 Jul 1;197(1):337-44. doi: 10.4049/jimmunol.1600280. Epub 2016 May, 18. PMID:27194791 doi:http://dx.doi.org/10.4049/jimmunol.1600280

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/5i5k"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[5i5k]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I5K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5I5K FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=5i5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i5k OCA], [http://pdbe.org/5i5k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i5k RCSB], [http://www.ebi.ac.uk/pdbsum/5i5k PDBsum]</span></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=5i5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i5k OCA], [http://pdbe.org/5i5k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i5k RCSB], [http://www.ebi.ac.uk/pdbsum/5i5k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i5k ProSAT]</span></td></tr>
 </table>
 == Disease ==

5i5k

From Proteopedia

Revision as of 18:01, 12 July 2016

Structure of complement C5 in complex with eculizumab

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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