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| | ==Ternary complex of human Complement C5 with Ornithodoros moubata OmCI and Rhipicephalus appendiculatus RaCI1== | | ==Ternary complex of human Complement C5 with Ornithodoros moubata OmCI and Rhipicephalus appendiculatus RaCI1== |
| - | <StructureSection load='5hce' size='340' side='right' caption='[[5hce]], [[Resolution|resolution]] 3.12Å' scene=''> | + | <StructureSection load='5hce' size='340' side='right'caption='[[5hce]], [[Resolution|resolution]] 3.12Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5hce]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Argasid_tick Argasid tick], [http://en.wikipedia.org/wiki/Brown_ear_tick Brown ear tick] 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=5HCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HCE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5hce]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Ornithodoros_moubata Ornithodoros moubata] and [https://en.wikipedia.org/wiki/Rhipicephalus_appendiculatus Rhipicephalus appendiculatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HCE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CYS:CYSTEINE'>CYS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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]] 3.12Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CI ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6938 Argasid tick])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CYS:CYSTEINE'>CYS</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=5hce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hce OCA], [http://pdbe.org/5hce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hce RCSB], [http://www.ebi.ac.uk/pdbsum/5hce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hce ProSAT]</span></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=5hce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hce OCA], [https://pdbe.org/5hce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hce RCSB], [https://www.ebi.ac.uk/pdbsum/5hce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hce ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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 == | | == 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5hce" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5hce" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Complement C5 3D structures|Complement C5 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Argasid tick]] | |
| - | [[Category: Brown ear tick]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Johnson, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Jore, M M]] | + | [[Category: Ornithodoros moubata]] |
| - | [[Category: Lea, S M]] | + | [[Category: Rhipicephalus appendiculatus]] |
| - | [[Category: Complement]] | + | [[Category: Johnson S]] |
| - | [[Category: Immune system]] | + | [[Category: Jore MM]] |
| - | [[Category: Inflammation]] | + | [[Category: Lea SM]] |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Tick]]
| + | |
| Structural highlights
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
Activation of complement C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic potential of C5 inhibition has been demonstrated by eculizumab, one of the world's most expensive drugs. However, the mechanism of C5 activation by C5 convertases remains elusive, thus limiting development of therapeutics. Here we identify and characterize a new protein family of tick-derived C5 inhibitors. Structures of C5 in complex with the new inhibitors, the phase I and phase II inhibitor OmCI, or an eculizumab Fab reveal three distinct binding sites on C5 that all prevent activation of C5. The positions of the inhibitor-binding sites and the ability of all three C5-inhibitor complexes to competitively inhibit the C5 convertase conflict with earlier steric-inhibition models, thus suggesting that a priming event is needed for activation.
Structural basis for therapeutic inhibition of complement C5.,Jore MM, Johnson S, Sheppard D, Barber NM, Li YI, Nunn MA, Elmlund H, Lea SM Nat Struct Mol Biol. 2016 May;23(5):378-86. doi: 10.1038/nsmb.3196. Epub 2016 Mar, 28. PMID:27018802[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jore MM, Johnson S, Sheppard D, Barber NM, Li YI, Nunn MA, Elmlund H, Lea SM. Structural basis for therapeutic inhibition of complement C5. Nat Struct Mol Biol. 2016 May;23(5):378-86. doi: 10.1038/nsmb.3196. Epub 2016 Mar, 28. PMID:27018802 doi:http://dx.doi.org/10.1038/nsmb.3196
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