Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs.
Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine, and ornithine analogs.
复制标题
使用 Ac-(D)Phe-Pro-boroArg-OH 及其赖氨酸、脒、高赖氨酸和鸟氨酸类似物进行凝血酶的动力学和晶体学研究。
作者：
P. Weber;S. L. Lee;F. Lewandowski;M. Schadt;C. W. Chang;C. Kettner
Ac-(D)Phe-Pro-boroArg-OH[DuP714，Ki=0.04 nm；Kettner，C.，MerSinger，L.，&Knabb，R.(1990)J.Biol]的X射线晶体结构。化学。265,18289]与人α-凝血酶络合显示，硼原子共价键合到活性部位丝氨酸的侧链氧上，丝氨酸195。硼采用接近四面体的几何构型，而硼酸与蛋白质形成一系列相互作用，模仿丝氨酸蛋白酶的四面体过渡态。精氨酸侧链对DUP714的鸟氨酸、赖氨酸、同型赖氨酸和嘧啶类似物的合成对抑制物亲和力的贡献进行了研究。碱性基团与主链羰基、水分子和位于凝血酶S1特异性口袋中的天冬氨酸侧链(Asp189)相互作用。抑制常数的3个数量级的变化似乎反映了与凝血酶相互作用的能量学的不同以及溶液中配体灵活性的不同。
The X-ray crystallographic structure of Ac-(D)Phe-Pro-boroArg-OH [DuP714, Ki = 0.04 nM; Kettner, C., Mersinger, L., & Knabb, R. (1990) J. Biol. Chem. 265, 18289] complexed with human alpha-thrombin shows the boron atom covalently bonded to the side-chain oxygen of the active site serine, Ser195. The boron adopts a nearly tetrahedral geometry, and the boronic acid forms a set of interactions with the protein that mimic the tetrahedral transition state of serine proteases. Contributions of the arginine side chain to inhibitor affinity were examined by synthesis of the ornithine, lysine, homolysine, and amidine analogs of DuP714. The basic groups interact with backbone carbonyl groups, water molecules, and an aspartic acid side chain (Asp189) located in the thrombin S1 specificity pocket. The variation in inhibition constant by 3 orders of magnitude appears to reflect differences in the energetics of interactions made with thrombin and differences in ligand flexibility in solution.(ABSTRACT TRUNCATED AT 250 WORDS)
登录
查看更多内容
影响因子：
1.1
作者：
FENTON, JW;OFOSU, FA;MARAGANORE, JM
通讯作者：
MARAGANORE, JM
影响因子：
3.8
作者：
J. Schellman
通讯作者：
J. Schellman
α-凝血酶的 hirugen 和 hirulog 1 复合物的结构。
影响因子：
5.6
作者：
Skrzypczak-Jankun,E;Carperos,VE;Ravichandran,KG;Tulinsky,A;Westbrook,M;Maraganore,JM
通讯作者：
Maraganore,JM
酶通过溶剂化取代而不是去溶剂化起作用。
DOI：
10.1073/pnas.86.15.5820
发表时间：
1989
影响因子：
11.1
作者：
Warshel,A;Aqvist,J;Creighton,S
通讯作者：
Creighton,S
碎片的过渡状态：熵效应对腺苷脱氨酶配体结合的主要贡献。
影响因子：
2.9
作者：
Kati,WM;Acheson,SA;Wolfenden,R
通讯作者：
Wolfenden,R