Structure of active coagulation factor XIII triggered by calcium binding: basis for the design of next-generation anticoagulants.
Structure of active coagulation factor XIII triggered by calcium binding: basis for the design of next-generation anticoagulants.
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钙结合触发的活性凝血因子XIII的结构：下一代抗凝剂设计的基础
DOI：
10.1002/anie.201305133
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发表时间：
2013
影响因子：
--
通讯作者：
Klebe G
中科院分区：
文献类型：
--
作者：
Stieler M;Weber J;Hils M;Kolb P;Heine A;Büchold C;Pasternack R;Klebe G
Remarkable effort has been devoted to develop drugs that target coagulation factors or platelet activation to prevent and treat thrombosis, pulmonary embolism, and acute coronary syndromes, or for reducing the risk of stroke in patients with atrial fibrillation. For decades, vitamin K antagonists were the only available anticoagulants that could be administered orally. Only recently, a new generation of direct-acting oral anticoagulants that block thrombin directly or indirectly via upstream factor Xa has become available.[1] However, depending on its activation state, thrombin can either promote or prevent blood clotting. Interference with thrombin activity by the currently available anticoagulants is characterized by an enhanced bleeding risk, thus excluding many patients from beneficial treatment.[2] The currently targeted enzymes of the blood-clotting cascade, namely factor Xa and thrombin, belong to the family of serine proteases. Remarkably, the final enzyme in the blood clotting cascade, coagulation factor XIII, shows a markedly different mode-of-action (see Figure S1 in the Supporting Information). It is a member of the transglutaminase family, and catalyzes the covalent cross-linking of protein chains bearing susceptible glutamine and lysine residues through isopeptide bonds.[3–6] In a blood clotting event, FXIII recognizes fibrin as the substrate and triggers clot maturation and accretion. In the case of congenital FXIII deficiency, delayed bleeding is reported as a clinical manifestation. Taking these considerations into account, FXIII is regarded as a prospective target to achieve potentially safer and more efficient thrombolysis at a lower dosage of clot-dissolving agents.[7] In fact, a FXIII inhibitor may even prevent thrombus formation altogether.[8]FXIII acts downstream of thrombin, effectively determining the mechanical stability, half-life, and lysis rate of clots. Although discussed as an ideal target to interfere with coagulation, no suitable drug candidates are available to explore the pharmacological potential of FXIII inhibition. This situation might also result from the fact that a protein structure representing a relevant active state of FXIII was previously unknown, but is necessary to embark on structurebased drug design. Here we report the first high-resolution crystal structure (1.98) of FXIII in an active state (termed FXIIIa8 in the following, as suggested by Muszbek et al.[9] for Ca2+ activation without proteolysis) in complex with an irreversibly bound inhibitor. Only crystal structures of inactive, homodimeric FXIII have been reported so far, where the active site is completely buried and any access to the catalytic center is obscured. Such structures are unsuitable for drug design. In the structure described herein, three calcium ions recruit polar functional groups of the protein and establish local metal ion coordination sites, which induce the rearrangement of two domains along with local adaptations of the catalytic domain to expose the enzyme in an active state. The observed transformations establish the substrate and cosubstrate binding sites for the formation of an isopeptide bond and suggest involvement of a catalytic triad and a newly identified diad in the enzyme mechanism which is considered valid for the entire transglutaminase family. Until now, very few FXIII inhibitors have been described. Finney et al.[10] reported that the 66 amino acid peptide tridegin from the salivary gland of the giant Amazon leech Haementeria ghilianii is a potent inhibitor. In the late 1980s, a series of small molecules that irreversibly inhibit FXIII were explored in animal models of thrombosis. As a result of the lack of selectivity along with the short plasma half-lives of only a few minutes …
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第 XIII 因素：推荐术语和缩写。
DOI：
--
发表时间：
2007
期刊：
J Thromb Haemost 5 (1)
影响因子：
--
作者：
Muszbek L
通讯作者：
Muszbek L
犬冠状动脉血栓模型中 XIIIa 因子的抑制：重组组织型纤溶酶原激活剂对再灌注和急性再闭塞的影响。
影响因子：
20.3
作者：
R. Shebuski;G. Sitko;D. Claremon;Jack J. Baldwin;David C. Remy;Andrew M. Stern
通讯作者：
Andrew M. Stern
DOI：
10.1073/pnas.91.15.7296
发表时间：
1994-07-19
影响因子：
11.1
作者：
YEE, VC;PEDERSEN, LC;TELLER, DC
通讯作者：
TELLER, DC
影响因子：
3.9
作者：
MARY, A;ACHYUTHAN, KE;GREENBERG, CS
通讯作者：
GREENBERG, CS
XIII 因子（纤维蛋白稳定因子）。
影响因子：
--
作者：
L. Lorand;R. Credo;T. Janus
通讯作者：
T. Janus