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| | ==Structural basis for therapeutic inhibition of complement C5== | | ==Structural basis for therapeutic inhibition of complement C5== |
| - | <StructureSection load='5iec' size='340' side='right' caption='[[5iec]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''> | + | <StructureSection load='5iec' size='340' side='right'caption='[[5iec]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5iec]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Brown_ear_tick Brown ear tick]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IEC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IEC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5iec]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rhipicephalus_appendiculatus Rhipicephalus appendiculatus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IEC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IEC 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=5iec FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iec OCA], [http://pdbe.org/5iec PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iec RCSB], [http://www.ebi.ac.uk/pdbsum/5iec PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5iec ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 10 models</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=5iec FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iec OCA], [https://pdbe.org/5iec PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5iec RCSB], [https://www.ebi.ac.uk/pdbsum/5iec PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5iec ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/C5I2_RHIMP C5I2_RHIMP] Complement inhibitor (PubMed:27018802). Prevents complement-mediated C5 activation by binding to C5 (PubMed:27018802). Binds C5 at a different binding site than the other tick complement inhibitors OmCI and CirpT1, and the drug eculizumab (By similarity).[UniProtKB:A0A146B485]<ref>PMID:27018802</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Brown ear tick]] | + | [[Category: Large Structures]] |
| - | [[Category: Lea, S M]] | + | [[Category: Rhipicephalus appendiculatus]] |
| - | [[Category: Sheppard, D]] | + | [[Category: Lea SM]] |
| - | [[Category: Blood clotting]] | + | [[Category: Sheppard D]] |
| - | [[Category: Complement inhibitor]]
| + | |
| - | [[Category: Raci]]
| + | |
| - | [[Category: Structure from cyana 3 96]]
| + | |
| Structural highlights
Function
C5I2_RHIMP Complement inhibitor (PubMed:27018802). Prevents complement-mediated C5 activation by binding to C5 (PubMed:27018802). Binds C5 at a different binding site than the other tick complement inhibitors OmCI and CirpT1, and the drug eculizumab (By similarity).[UniProtKB:A0A146B485][1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ 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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