5b71

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of complement C5 in complex with SKY59

Structural highlights

5b71 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.11Å
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

Dysregulation of the complement system is linked to the pathogenesis of a variety of hematological disorders. Eculizumab, an anti-complement C5 monoclonal antibody, is the current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). However, because of high levels of C5 in plasma, eculizumab has to be administered biweekly by intravenous infusion. By applying recycling technology through pH-dependent binding to C5, we generated a novel humanized antibody against C5, SKY59, which has long-lasting neutralization of C5. In cynomolgus monkeys, SKY59 suppressed C5 function and complement activity for a significantly longer duration compared to a conventional antibody. Furthermore, epitope mapping by X-ray crystal structure analysis showed that a histidine cluster located on C5 is crucial for the pH-dependent interaction with SKY59. This indicates that the recycling effect of SKY59 is driven by a novel mechanism of interaction with its antigen and is distinct from other known pH-dependent antibodies. Finally, SKY59 showed neutralizing effect on C5 variant p.Arg885His, while eculizumab does not inhibit complement activity in patients carrying this mutation. Collectively, these results suggest that SKY59 is a promising new anti-C5 agent for patients with PNH and other complement-mediated disorders.

Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases.,Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, Gan SW, Irie M, Tsuboi Y, Tai H, Sakiyama T, Sakamoto A, Ishii S, Maeda A, Iwayanagi Y, Shibahara N, Shibuya M, Nakamura G, Nambu T, Hayasaka A, Mimoto F, Okura Y, Hori Y, Habu K, Wada M, Miura T, Tachibana T, Honda K, Tsunoda H, Kitazawa T, Kawabe Y, Igawa T, Hattori K, Nezu J Sci Rep. 2017 Apr 24;7(1):1080. doi: 10.1038/s41598-017-01087-7. PMID:28439081^[1]

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

References

↑ Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, Gan SW, Irie M, Tsuboi Y, Tai H, Sakiyama T, Sakamoto A, Ishii S, Maeda A, Iwayanagi Y, Shibahara N, Shibuya M, Nakamura G, Nambu T, Hayasaka A, Mimoto F, Okura Y, Hori Y, Habu K, Wada M, Miura T, Tachibana T, Honda K, Tsunoda H, Kitazawa T, Kawabe Y, Igawa T, Hattori K, Nezu J. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci Rep. 2017 Apr 24;7(1):1080. doi: 10.1038/s41598-017-01087-7. PMID:28439081 doi:http://dx.doi.org/10.1038/s41598-017-01087-7

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5b71"

@@ Line 1: / Line 1: @@
 ==Crystal structure of complement C5 in complex with SKY59==
-<StructureSection load='5b71' size='340' side='right' caption='[[5b71]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
+<StructureSection load='5b71' size='340' side='right'caption='[[5b71]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5b71]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5B71 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5B71 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5b71]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5B71 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5B71 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=5b71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5b71 OCA], [http://pdbe.org/5b71 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5b71 RCSB], [http://www.ebi.ac.uk/pdbsum/5b71 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5b71 ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5b71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5b71 OCA], [https://pdbe.org/5b71 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5b71 RCSB], [https://www.ebi.ac.uk/pdbsum/5b71 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5b71 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/CO5_HUMAN CO5_HUMAN]] Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:[http://omim.org/entry/609536 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).
+[https://www.uniprot.org/uniprot/CO5_HUMAN CO5_HUMAN] Defects in C5 are the cause of complement component 5 deficiency (C5D) [MIM:[https://omim.org/entry/609536 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 ==
-[[http://www.uniprot.org/uniprot/CO5_HUMAN 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).
+[https://www.uniprot.org/uniprot/CO5_HUMAN 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).
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 5b71" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Complement C5 3D structures|Complement C5 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Fukuzawa, T]]
+[[Category: Homo sapiens]]
-[[Category: Irie, M]]
+[[Category: Large Structures]]
-[[Category: Sampei, Z]]
+[[Category: Fukuzawa T]]
-[[Category: Shimizu, Y]]
+[[Category: Irie M]]
-[[Category: Complement c5]]
+[[Category: Sampei Z]]
-[[Category: Complex]]
+[[Category: Shimizu Y]]
-[[Category: Fab]]
-[[Category: Immune system]]
-[[Category: Ph-dependent]]
-[[Category: Recycling antibody]]

5b71

From Proteopedia

Current revision

Crystal structure of complement C5 in complex with SKY59

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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