Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin.
Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin.
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硅烷二醇作为基准金属蛋白酶嗜热菌蛋白酶过渡态类似物抑制剂的结构分析。
DOI：
10.1021/bi051346v
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Sieburth,ScottMcN
中科院分区：
文献类型：
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作者：
Juers,DouglasH;Kim,Jaeseung;Matthews,BrianW;Sieburth,ScottMcN
已发现二烷基硅烷二醇是用于设计活性位点定向的蛋白酶抑制剂的有效官能团，所述蛋白酶抑制剂包括天冬氨酸（HIV蛋白酶）和金属（ACE和嗜热菌蛋白酶）蛋白酶。硅烷二醇的使用是基于其与酰胺水解的水合羰基过渡态结构的相似性。这一概念已通过用硅二醇基团取代嗜热菌蛋白酶底物的假定四面体碳进行了测试，产生了抑制常数Ki = 40 nM的抑制剂。结合到嗜热菌蛋白酶的活性位点的硅烷二醇的结构被发现具有与相应的磷酰胺抑制剂（Ki= 10 nM）非常相似的构象。在这两种情况下，一个单一的氧是在键合距离内的活性位点的锌离子，模仿假定的四面体过渡态。存在结合差异，其似乎与连接到硅或磷的氧上的质子的存在或不存在有关。这是结合到蛋白酶活性位点的有机硅烷的第一种晶体结构。
Dialkylsilanediols have been found to be an effective functional group for the design of active-site-directed protease inhibitors, including aspartic (HIV protease) and metallo (ACE and thermolysin) proteases. The use of silanediols is predicated on its resemblance to the hydrated carbonyl transition-state structure of amide hydrolysis. This concept has been tested by replacing the presumed tetrahedral carbon of a thermolysin substrate with a silanediol group, resulting in an inhibitor with an inhibition constantKi= 40 nM. The structure of the silanediol bound to the active site of thermolysin was found to have a conformation very similar to that of a corresponding phosphonamidate inhibitor (Ki= 10 nM). In both cases, a single oxygen is within bonding distance to the active-site zinc ion, mimicking the presumed tetrahedral transition state. There are binding differences that appear to be related to the presence or absence of protons on the oxygens attached to the silicon or phosphorus. This is the first crystal structure of an organosilane bound to the active site of a protease.