Structure-based design of a periplasmic binding protein antagonist that prevents domain closure.
Structure-based design of a periplasmic binding protein antagonist that prevents domain closure.
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DOI：
10.1021/cb900021q
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发表时间：
2009-06-19
影响因子：
4
通讯作者：
Kiessling, Laura L.
中科院分区：
文献类型：
--
作者：
Borrok, M. Jack;Zhu, Yimin;Forest, Katrina T.;Kiessling, Laura L.
许多受体经历配体诱导的构象变化以启动信号转导。周质结合蛋白（Periplasmic binding proteins，PBPs）是一类与配体结合后构象发生剧烈变化的细菌受体。这些蛋白质介导各种各样的基本过程，包括运输，趋化性和群体感应。尽管这些受体的重要性，没有PBP拮抗剂已被确定和表征。在这项研究中，我们确定3-O-甲基-D-葡萄糖作为葡萄糖/半乳糖结合蛋白的拮抗剂，并证明它抑制E.杆菌使用小角X射线散射和X射线晶体学，我们表明，这种拮抗剂作为一个楔子。它可以防止大规模的结构域闭合，从而产生活跃的信号状态。在此基础上，结合葡萄糖/半乳糖结合蛋白的结构，我们设计并合成了一个由两个葡萄糖残基连接而成的拮抗剂。这些发现为设计新的细菌PBP抑制剂提供了蓝图。鉴于PBP在微生物生理学中的关键作用，我们预计PBP拮抗剂将作为探针和抗微生物剂具有广泛的用途。
Many receptors undergo ligand-induced conformational changes to initiate signal transduction. Periplasmic binding proteins (PBPs) are bacterial receptors that exhibit dramatic conformational changes upon ligand binding. These proteins mediate a wide variety of fundamental processes including transport, chemotaxis, and quorum sensing. Despite the importance of these receptors, no PBP antagonists have been identified and characterized. In this study, we identify 3-O-methyl-D-glucose as an antagonist of glucose/galactose binding protein and demonstrate that it inhibits glucose chemotaxis in E. coli. Using small angle X-ray scattering and X-ray crystallography, we show that this antagonist acts as a wedge. It prevents the large-scale domain closure that gives rise to the active signaling state. Guided by these results and the structures of open and closed glucose/galactose binding protein, we designed and synthesized an antagonist composed of two linked glucose residues. These findings provide a blueprint for the design of new bacterial PBP inhibitors. Given the key role of PBPs in microbial physiology, we anticipate that PBP antagonists will have widespread uses as probes and antimicrobial agents.
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影响因子：
3.2
作者：
ADLER, J;HAZELBAUER, GL;DAHL, MM
通讯作者：
DAHL, MM
影响因子：
--
作者：
Gestwicki, JE;Strong, LE;Kiessling, LL
通讯作者：
Kiessling, LL
影响因子：
64.8
作者：
Hollenstein, Kaspar;Frei, Dominik C.;Locher, Kaspar P.
通讯作者：
Locher, Kaspar P.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
2.9
作者：
Amsler, CD
通讯作者：
Amsler, CD