The structure of a designed peptidomimetic inhibitor complex of alpha-thrombin.
The structure of a designed peptidomimetic inhibitor complex of alpha-thrombin.
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设计的α-凝血酶拟肽抑制剂复合物的结构。
DOI：
10.1093/protein/6.5.471
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Kahn,M
中科院分区：
文献类型：
--
作者：
Wu,TP;Yee,V;Tulinsky,A;Chrusciel,RA;Nakanishi,H;Shen,R;Priebe,C;Kahn,M
凝血酶具有显著的特异性，通过选择性地断裂纤维蛋白原181Arg/Lys-Xaa键之间的两个Arg-Gly键，影响纤维蛋白原的纤维蛋白多肽A和B的去除。近年来，在了解人类纤维蛋白原Aα链的Arg6-Gly17键断裂的特异性的起源方面取得了重大进展。我们以前基于核磁共振数据、计算机辅助分子模拟以及模拟凝血酶的多肽底物和抑制剂的合成和研究，提出了纤维蛋白多肽A7-16(FPA)的结合结构模型。我们现在报道了FPA模拟物(FPAM)、水飞蓟素和凝血酶的三元复合体的结构(R因子=0.138)，以及FPAM抑制凝血酶和相关的胰酶样蛋白酶的特异性数据。测定了FPA及其与凝血酶结合的氯甲酮衍生物的晶体结构。尽管这些结构与凝血酶结合的FPAM的晶体结构有所不同，但所有结构中P1-P2-P3临界区的φ，ψ角都与BPTI-胰酶复合体中的牛胰蛋白酶抑制剂和PPACK-凝血酶结构中的D-Phe-Pro-Arg(PPACK)相似。并与一种核磁共振衍生结构进行了比较和讨论。
Thrombin displays remarkable specificity, effecting the removal of fibrinopeptides A and B of fibrinogen through the selective cleavage of two Arg–Gly bonds between the 181 Arg/Lys–Xaa bonds in fibrinogen. Significant advances have been made in recent years towards understanding the origin of the specificity of cleavage of the Argl6–Gly17 bond of the Aα-chain of human fibrinogen. We have previously proposed a model for the bound structure of fibrinopeptide A7–16(FPA), based upon NMR data, computer-assisted molecular modeling and the synthesis and study of peptidomimetic substrates and inhibitors of thrombin. We now report the structure of the ternary complex of an FPA mimetic (FPAM), hirugen and thrombin at 2.5 Å resolution (R-factor = 0.138) and specificity data for the inhibition of thrombin and related trypsin-like proteinases by FPAM. The crystallographic structures of FPA and its chloromethyl ketone derivative bound to thrombin were determined. Although there are differences between these structures in the above modeled FPA structure and that of the crystal structure of FPAM bound to thrombin, the φ, ψ angles in the critical region of P1–P2–P3 in all of the structures are similar to those of bovine pancreatic trypsin inhibitor (BPTI) in the BPTI–trypsin complex and D–Phe–Pro–Arg (PPACK) in the PPACK–thrombin structure. A comparison between these and an NMR-derived structure is carried out and discussed.