Replacement of water molecules in a phosphate binding site by furanoside-appended lin-benzoguanine ligands of tRNA-guanine transglycosylase (TGT).
Replacement of water molecules in a phosphate binding site by furanoside-appended lin-benzoguanine ligands of tRNA-guanine transglycosylase (TGT).
复制标题
用 tRNA-鸟嘌呤转糖基酶 (TGT) 的呋喃糖苷 lin-苯鸟嘌呤配体取代磷酸盐结合位点中的水分子
DOI：
10.1002/chem.201405764
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
F. Diederich
中科院分区：
文献类型：
--
作者：
L.J. Barandun;F.R. Ehrmann;D.Zimmerli;F. Immekus;M. Giroud;C. Grünenfelder;W.B. Schweizer;B. Bernet;M. Betz;A. Heine;G. Klebe;F. Diederich
酶tRNA-鸟嘌呤转糖基酶已被确定为食源性疾病志贺氏菌病的药物靶点。这种酶基于结构设计的一个关键挑战是极性核糖-34口袋的填充。在此，我们描述了一系列由呋喃糖苷-附加的lin-苯并鸟嘌呤组成的新型配体。它们被设计为取代保守的水簇，并且不同之处在于呋喃糖基部分的C（2）和C（3）处的官能团是OH或OMe。Asp 102和Asp 280（靠近核糖-34口袋）的不利去溶剂化对结合亲和力有显著影响。虽然该酶以tRNA作为其天然底物，但X射线共晶结构显示配体的呋喃糖基部分并不位于tRNA核糖-34位点，而是位于相邻磷酸基团的位置。这两种结构中氧原子位置的显著相似性表明呋喃糖苷是潜在的磷酸盐等排体。
The enzyme tRNA‐guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure‐based design for this enzyme is the filling of the polar ribose‐34 pocket. Herein, we describe a novel series of ligands consisting of furanoside‐appendedlin‐benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose‐34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X‐ray co‐crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose‐34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.
登录
查看更多内容
如何替换极性活性位点残基的残留溶剂化壳以实现tRNA-鸟嘌呤转糖基酶的纳摩尔抑制
影响因子：
3.4
作者：
T. Ritschel;Philipp Kohler;G. Neudert;A. Heine;F. Diederich;G. Klebe
通讯作者：
G. Klebe
影响因子：
16.6
作者：
Ellermann, Manuel;Jakob-Roetne, Roland;Diederich, Francois
通讯作者：
Diederich, Francois
影响因子：
7.3
作者：
Amadasi, Alessio;Surface, J. Andrew;Kellogg, Glen E.
通讯作者：
Kellogg, Glen E.
量化水在蛋白质-碳水化合物相互作用中的作用。
DOI：
10.1021/jp035027u
发表时间：
2003
期刊：
The journal of physical chemistry. A
影响因子：
--
作者：
Tschampel,SarahM;Woods,RobertJ
通讯作者：
Woods,RobertJ
影响因子：
4
作者：
Immekus, Florian;Barandun, Luzi Jakob;Klebe, Gerhard
通讯作者：
Klebe, Gerhard