期刊
SCIENCE
卷 330, 期 6012, 页码 1816-1820出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1195821
关键词
-
资金
- Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) [700.54.304]
- NIH [AI030040, AI068730, AI072106, GM062134]
Activation of the complement cascade induces inflammatory responses and marks cells for immune clearance. In the central complement-amplification step, a complex consisting of surface-bound C3b and factor B is cleaved by factor D to generate active convertases on targeted surfaces. We present crystal structures of the pro-convertase C3bB at 4 angstrom resolution and its complex with factor D at 3.5 angstrom resolution. Our data show how factor B binding to C3b forms an open activation state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D's self-inhibitory loop. This concerted proteolytic mechanism, which is cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.
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