GEOMETRY OF BINDING OF THE BENZAMIDINE-BASED AND ARGININE-BASED INHIBITORS N-ALPHA-(2-NAPHTHYL-SULFONYL-GLYCYL)-DL-PARA-AMIDINOPHENYLALANYL-PIPERIDINE (NAPAP) AND (2R,4R)-4-METHYL-1-[N-ALPHA-(3-METHYL-1,2,3,4-TETRAHYDRO-8-QUINOLINESULPHONYL)-L-ARGINYL]-2-PIPERIDINE CARBOXYLIC-ACID (MQPA) TO HUMAN ALPHA-THROMBIN - X-RAY CRYSTALLOGRAPHIC DETERMINATION OF THE NAPAP-TRYPSIN COMPLEX AND MODELING OF NAPAP-THROMBIN AND MQPA-THROMBIN
GEOMETRY OF BINDING OF THE BENZAMIDINE-BASED AND ARGININE-BASED INHIBITORS N-ALPHA-(2-NAPHTHYL-SULFONYL-GLYCYL)-DL-PARA-AMIDINOPHENYLALANYL-PIPERIDINE (NAPAP) AND (2R,4R)-4-METHYL-1-[N-ALPHA-(3-METHYL-1,2,3,4-TETRAHYDRO-8-QUINOLINESULPHONYL)-L-ARGINYL]-2-PIPERIDINE CARBOXYLIC-ACID (MQPA) TO HUMAN ALPHA-THROMBIN - X-RAY CRYSTALLOGRAPHIC DETERMINATION OF THE NAPAP-TRYPSIN COMPLEX AND MODELING OF NAPAP-THROMBIN AND MQPA-THROMBIN
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DOI：
10.1111/j.1432-1033.1990.tb19320.x
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发表时间：
1990-10-05
期刊：
影响因子：
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通讯作者：
STURZEBECHER, J
中科院分区：
文献类型：
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作者：
BODE, W;TURK, D;STURZEBECHER, J
用N α-胰蛋白酶形成的胰蛋白酶复合物的X射线晶体结构本文报道了（2-萘磺酰-乙二醇）-DL-对脒基苯丙氨酰-哌啶（NAPAP）的X射线衍射测定，其分辨率为0.18nm，并进行了晶体学修正。NAPAP以非常紧密的形式结合到胰蛋白酶的活性位点：D-立体异构体的p-脒基苯丙氨酸部分结合到特异性口袋中;甘氨酰基与Gly 216氢键合;萘基与Trp 215的吲哚部分垂直;哌啶环紧密地堆积在该萘基部分和His 57之间;因此，NAPAP的羧基末端酰胺键以这样的方式定位，即它对活性位点Ser 195不敏感。NAPAP和（2 R，4 R）-4-甲基-1-[N α-（3-甲基-1，2，3，4-四氢-8-喹啉磺酰基）-L-异丙基]-2-哌啶羧酸（MQPA）[Matzusaki，T.，Sasaki，C.，奥村角和Umeyama（1989）J. Biochem.（Tokyo）105，949-952]以其胰蛋白酶结合构象转移到人α-凝血酶[Bode，W.，迈尔岛，鲍曼，美国，胡贝尔河，巴西-地斯通，S。R.和Hofsteenge，J.（1989）EMBO J.8，3467 - 3475]，并且能量最小化。这两种合成抑制剂都完全适合凝血酶的活性部位。凝血酶的“芳基结合位点”中的S-芳基部分和S2亚位点中的哌啶环的容纳是特别有利的。凝血酶对不同取代的哌啶衍生物的偏好以及其对苯甲脒和基于精氨酸的抑制剂的通常较高的亲和力（与胰蛋白酶相比）可以通过这些凝血酶抑制剂模型来解释。
The X-ray crystal structure of the trypsin complex formed with N.alpha.-(2-naphthyl-sulfonyl-glycl)-DL-p-amidinophenylalanyl-piperidine (NAPAP) was determiend with X-ray data to 0.18-nm resolution and crystallographically refined. NAPAP binds into the active site of trypsin in a quite compact form: the p-amidinophenylalanine moiety of the D-stereoisomer binds into the specificity pocket; the glycyl group is hydrogen bonded with Gly216; the naphthyl group stands perpendicular to the indole moiety of Trp215; the piperidine ring is tightly packed between this naphthyl moiety and His57; in consequence the carboxy-terminal amido bond of NAPAP is located in such a way that it is not susceptible to the active-site Ser195. NAPAP and (2R,4R)-4-methyl-1-[N.alpha.-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulphonyl)-L-arginyl]-2-piperidine carboxylic acid (MQPA) [Matzusaki, T., Sasaki, C., Okumura, C. and Umeyama (1989) J. Biochem. (Tokyo) 105, 949-952] were transferred in their trypsin-binding conformations to human .alpha.-thrombin [Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S. R. and Hofsteenge, J. (1989) EMBO J. 8, 3467 - 3475] and energy minimized. Both synthetic inhibitors fit perfectly into the much more restricted active site of thrombin. The accomodation of the S-aryl moieties in the ''aryl-binding site'' and of the piperidine rings in the S2 subsite of thrombin are particularly favourable. The preference of thrombin for distinctly substituted piperidine derivatives and its generally higher (compared with trypsin) affinity for benzamidine and arginine-based inhibitors can be accounted for by these thrombin inhibitor models.