Insights into the binding of pyridines to the iron-sulfur enzyme IspH.
Insights into the binding of pyridines to the iron-sulfur enzyme IspH.
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DOI：
10.1021/ja501127j
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发表时间：
2014-06-04
影响因子：
15
通讯作者：
Groll, Michael
中科院分区：
文献类型：
--
作者：
Span, Ingrid;Wang, Ke;Eisenreich, Wolfgang;Bacher, Adelbert;Zhang, Yong;Oldfield, Eric;Groll, Michael
(E)-1-羟基-2-甲基-2-烯基-4-二磷酸还原酶(IspH)是一种含有[Fe4S4]簇的酶，参与许多细菌以及疟疾寄生虫中类异戊二烯的生物合成，是重要的药物靶标。已经报道了几种抑制剂，包括氨基和硫醇底物类似物，以及乙炔和吡啶二磷酸盐。在这里，我们用X射线结晶学的方法研究了四种吡啶二磷酸与大肠杆菌IspH的结合方式。在三种情况下，簇中的一个铁原子缺失，但在先前报道的最有效的吡啶类似物抑制剂(吡啶-3-基)甲基二磷酸的结构中，存在[Fe4S4]簇中的第四个铁原子，并与配体的吡啶环相互作用。基于量子化学计算结果和结晶学结果，我们提出了吡啶环2-位的氮和碳与团簇中唯一的处于还原状态的第四铁的η-2配位。X射线结构使得使用密度泛函理论对先前使用HYSCORE光谱报道的14N超精细耦合和四极耦合常数进行了出色的预测，并提供了含有[Fe4S4]的蛋白质形成有机金属络合物的能力的进一步例子。
(E)-1-Hydroxy-2-methylbut-2-enyl 4-diphosphate reductase (IspH) is a [Fe4S4] cluster-containing enzyme involved in isoprenoid biosynthesis in many bacteria as well as in malaria parasites and is an important drug target. Several inhibitors including amino and thiol substrate analogues, as well as acetylene and pyridine diphosphates, have been reported. Here, we investigate the mode of binding of four pyridine diphosphates to Escherichia coli IspH by using X-ray crystallography. In three cases, one of the iron atoms in the cluster is absent, but in the structure with (pyridin-3-yl)methyl diphosphate, the most potent pyridine-analogue inhibitor reported previously, the fourth iron of the [Fe4S4] cluster is present and interacts with the pyridine ring of the ligand. Based on the results of quantum chemical calculations together with the crystallographic results we propose a side-on η2 coordination of the nitrogen and the carbon in the 2-position of the pyridine ring to the unique fourth iron in the cluster, which is in the reduced state. The X-ray structure enables excellent predictions using density functional theory of the 14N hyperfine coupling and quadrupole coupling constants reported previously using HYSCORE spectroscopy, as well as providing a further example of the ability of such [Fe4S4]-containing proteins to form organometallic complexes.
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影响因子：
18.3
作者：
Oldfield, Eric
通讯作者：
Oldfield, Eric
影响因子：
16.6
作者：
Ahrens-Botzong, Annegret;Janthawornpong, Karnjapan;Wolny, Juliusz A.;Tambou, Erasmienne Ngouamegne;Rohmer, Michel;Krasutsky, Sergiy;Poulter, C. Dale;Schuenemann, Volker;Seemann, Myriam
通讯作者：
Seemann, Myriam
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：
16.6
作者：
Graewert, Tobias;Rohdich, Felix;Groll, Michael
通讯作者：
Groll, Michael
DOI：
10.1073/pnas.79.4.1096
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
KENT, TA;DREYER, JL;MUNCK, E
通讯作者：
MUNCK, E