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-Structure paper
タイトル | Structural basis for therapeutic inhibition of complement C5. |
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ジャーナル・号・ページ | Nat Struct Mol Biol, Vol. 23, Issue 5, Page 378-386, Year 2016 |
掲載日 | 2016年3月28日 |
![]() | Matthijs M Jore / Steven Johnson / Devon Sheppard / Natalie M Barber / Yang I Li / Miles A Nunn / Hans Elmlund / Susan M Lea / ![]() ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) / X線回折 / NMR (溶液) |
解像度 | 2.59 - 16.0 Å |
構造データ | ![]() EMDB-8092: ![]() PDB-5hcc: ![]() PDB-5hcd: ![]() PDB-5hce: ![]() PDB-5iec: |
化合物 | ![]() ChemComp-EDO: ![]() ChemComp-CYS: ![]() ChemComp-DIO: ![]() ChemComp-HOH: |
由来 |
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![]() | IMMUNE SYSTEM / Complement / Inflammation / Inhibitor / Tick / BLOOD CLOTTING / complement inhibitor / RaCI / STRUCTURE FROM CYANA 3.96 |