Jore Matthijs M, Johnson Steven, Sheppard Devon, Barber Natalie M, Li Yang I, Nunn Miles A, Elmlund Hans, Lea Susan M
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Nat Struct Mol Biol. 2016 May;23(5):378-86. doi: 10.1038/nsmb.3196. Epub 2016 Mar 28.
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.
补体C5的激活会产生强效过敏毒素C5a，并导致病原体裂解、炎症和细胞损伤。依库珠单抗已证明了C5抑制的治疗潜力，它是世界上最昂贵的药物之一。然而，C5转化酶激活C5的机制仍然难以捉摸，从而限制了治疗药物的开发。在此，我们鉴定并表征了一个新的蜱源C5抑制剂蛋白家族。C5与新抑制剂、I期和II期抑制剂OmCI或依库珠单抗Fab形成的复合物结构揭示了C5上三个不同的结合位点，这些位点均能阻止C5的激活。抑制剂结合位点的位置以及所有三种C5-抑制剂复合物竞争性抑制C5转化酶的能力与早期的空间抑制模型相矛盾，因此表明激活需要一个启动事件。
