Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent.
Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent.
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DOI：
10.1016/j.str.2017.12.010
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发表时间：
2018-02-06
期刊：
影响因子：
--
通讯作者：
Coughlin SR
中科院分区：
文献类型：
--
作者：
Ely LK;Lolicato M;David T;Lowe K;Kim YC;Samuel D;Bessette P;Garcia JL;Mikita T;Minor DL Jr;Coughlin SR
凝血因子XIa是抗凝剂的候选靶点，可以更好地将抗血栓疗效与出血风险分开。我们报告了FXIa蛋白酶结构域与DEF的共晶体结构，DEF是一种人单克隆抗体，可阻断FXIa功能并预防动物模型中的血栓形成，而不会明显增加出血。DEF的轻链封闭FXIa S1亚位点和活性位点，而重链提供与FXIa表面的静电相互作用。该结构解释了DEF对FXIa相对于其酶原和相关蛋白酶的特异性、其活性位点依赖性结合及其抑制底物裂解的能力。用于获得DEF-FXIa晶体结构的失活FXIa蛋白酶结构域逆转了血浆和体内DEF的抗凝活性以及体外小分子FXIa活性位点抑制剂的活性。DEF和FXIa活性位点抑制剂的逆转剂可能有助于支持FXIa靶向抗凝剂的临床开发。抑制凝血因子XI（FXI）可以预防血栓形成，同时减少出血。DEF是一种阻断FXI活性形式（FXIa）的人单克隆抗体。伊利等人描述了一种结构，解释了DEF对FXIa的抗凝功能和特异性，并确定了FXIa抑制剂的解毒剂。
Coagulation factor XIa is a candidate target for anticoagulants that better separate antithrombotic efficacy from bleeding risk. We report a co-crystal structure of the FXIa protease domain with DEF, a human monoclonal antibody that blocks FXIa function and prevents thrombosis in animal models without detectably increased bleeding. The light chain of DEF occludes the FXIa S1 subsite and active site while the heavy chain provides electrostatic interactions with the surface of FXIa. The structure accounts for the specificity of DEF for FXIa over its zymogen and related proteases, its active site-dependent binding, and its ability to inhibit substrate cleavage. The inactive FXIa protease domain used to obtain the DEF-FXIa crystal structure reversed anticoagulant activity of DEF in plasma and in vivo and the activity of a small molecule FXIa active-site inhibitor in vitro. DEF and this reversal agent for FXIa active-site inhibitors may help support clinical development of FXIa-targeting anticoagulants. Inhibition of coagulation factor XI (FXI) may prevent thrombosis with less bleeding. DEF is a human monoclonal antibody that blocks the active form of FXI (FXIa). Ely et al. describe a structure that explains the anticoagulant function and specificity of DEF for FXIa, and identifies an antidote for FXIa inhibitors.
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发表时间：
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期刊：
The New England journal of medicine
影响因子：
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作者：
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期刊：
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影响因子：
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10.1073/pnas.93.13.6258
发表时间：
1996-06-25
影响因子：
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作者：
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