Mol C D, Arvai A S, Sanderson R J, Slupphaug G, Kavli B, Krokan H E, Mosbaugh D W, Tainer J A
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
Cell. 1995 Sep 8;82(5):701-8. doi: 10.1016/0092-8674(95)90467-0.
Uracil-DNA glycosylase inhibitor (Ugi) is a B. subtilis bacteriophage protein that protects the uracil-containing phage DNA by irreversibly inhibiting the key DNA repair enzyme uracil-DNA glycosylase (UDG). The 1.9 A crystal structure of Ugi complexed to human UDG reveals that the Ugi structure, consisting of a twisted five-stranded antiparallel beta sheet and two alpha helices, binds by inserting a beta strand into the conserved DNA-binding groove of the enzyme without contacting the uracil specificity pocket. The resulting interface, which buries over 1200 A2 on Ugi and involves the entire beta sheet and an alpha helix, is polar and contains 22 water molecules. Ugi binds the sequence-conserved DNA-binding groove of UDG via shape and electrostatic complementarity, specific charged hydrogen bonds, and hydrophobic packing enveloping Leu-272 from a protruding UDG loop. The apparent mimicry by Ugi of DNA interactions with UDG provides both a structural mechanism for UDG binding to DNA, including the enzyme-assisted expulsion of uracil from the DNA helix, and a crystallographic basis for the design of inhibitors with scientific and therapeutic applications.
尿嘧啶-DNA糖基化酶抑制剂（Ugi）是一种枯草芽孢杆菌噬菌体蛋白，它通过不可逆地抑制关键的DNA修复酶尿嘧啶-DNA糖基化酶（UDG）来保护含尿嘧啶的噬菌体DNA。与人类UDG复合的Ugi的1.9埃晶体结构表明，Ugi结构由一个扭曲的五链反平行β折叠和两个α螺旋组成，通过将一条β链插入酶的保守DNA结合凹槽而结合，不接触尿嘧啶特异性口袋。由此形成的界面在Ugi上掩埋了超过1200埃²，涉及整个β折叠和一个α螺旋，是极性的，包含22个水分子。Ugi通过形状和静电互补、特定的带电氢键以及包裹来自突出的UDG环的亮氨酸-272的疏水堆积，与UDG的序列保守DNA结合凹槽结合。Ugi对DNA与UDG相互作用的明显模拟，既为UDG与DNA结合提供了一种结构机制，包括酶辅助将尿嘧啶从DNA螺旋中排出，也为具有科学和治疗应用的抑制剂设计提供了晶体学基础。
