Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: new lead exhibits a distinct binding mode.
Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: new lead exhibits a distinct binding mode.
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DOI：
10.1016/j.bmc.2012.05.060
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Ji, Xinhua
中科院分区：
文献类型：
--
作者：
Shi, Genbin;Shaw, Gary;Li, Yue;Wu, Yan;Yan, Honggao;Ji, Xinhua
6-羟甲基-7，8-二氢蝶呤焦磷酸激酶（6-Hydroxymethyl-7，8-dihydropterin pyrophosphokinase，HPPK）是叶酸生物合成途径中的关键酶，催化ATP向6-羟甲基-7，8-二氢蝶呤的焦磷酸转移，是开发新型抗菌药物的重要靶点。在此之前，我们研究了HPPK的作用机制，通过将6-羟甲基蝶呤通过磷酸基团连接到腺苷来合成双底物类似物抑制剂，并通过用含哌啶的连接取代磷酸桥来开发新一代双底物抑制剂。为了进一步改善接头特性，我们合成了一种新化合物，表征了其蛋白质结合/抑制特性，并确定了其与HPPK复合的结构。令人惊讶的是，这种抑制剂表现出一种新的结合模式，即腺嘌呤碱基翻转时，与以前报道的结构相比。此外，氨基酸残基E77的侧链参与蛋白质-抑制剂相互作用，与核糖部分的2'和3'羟基形成氢键。残基E77在HPPK序列中是保守的，但仅通过水分子与结合的MgATP间接相互作用。以前从未观察到，E77-核糖相互作用仅与新的寡核苷酸结合模式相容。因此，该化合物代表了进一步开发的新方向。
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthesis pathway catalyzing the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin, is an attractive target for developing novel antimicrobial agents. Previously, we studied the mechanism of HPPK action, synthesized bisubstrate analogue inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed a new generation of bisubstrate inhibitors by replacing the phosphate bridge with a piperidine-containing linkage. To further improve linker properties, we have synthesized a new compound, characterized its protein binding/inhibiting properties, and determined its structure in complex with HPPK. Surprisingly, this inhibitor exhibits a new binding mode in that the adenine base is flipped when compared to previously reported structures. Furthermore, the side chain of amino acid residue E77 is involved in protein-inhibitor interaction, forming hydrogen bonds with both 2' and 3' hydroxyl groups of the ribose moiety. Residue E77 is conserved among HPPK sequences, but interacts only indirectly with the bound MgATP via water molecules. Never observed before, the E77-ribose interaction is compatible only with the new inhibitor-binding mode. Therefore, this compound represents a new direction for further development.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
COHEN, ML
通讯作者：
COHEN, ML
影响因子：
5.6
作者：
Hennig, M;Dale, GE;Oefner, C
通讯作者：
Oefner, C
影响因子：
3.5
作者：
Shi, Genbin;Shaw, Gary;Liang, Yu-He;Subburaman, Priadarsini;Li, Yue;Wu, Yan;Yan, Honggao;Ji, Xinhua
通讯作者：
Ji, Xinhua
DOI：
10.1002/prot.10286
发表时间：
2003-02-15
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Lovell, SC;Davis, IW;Richardson, DC
通讯作者：
Richardson, DC