Structural Basis for the Binding of the Anticancer Compound 6-(7-Nitro-2,1,3-Benzoxadiazol-4-Ylthio)Hexanol to Human Glutathione S-Transferases
Structural Basis for the Binding of the Anticancer Compound 6-(7-Nitro-2,1,3-Benzoxadiazol-4-Ylthio)Hexanol to Human Glutathione S-Transferases
复制标题
DOI：
10.1158/0008-5472.can-09-1314
复制
发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Caccuri, Anna Maria
中科院分区：
文献类型：
--
作者：
Federici, Luca;Lo Sterzo, Carlo;Caccuri, Anna Maria
谷胱甘肽S转移酶(GST)是一个超家族酶，具有多种功能，包括对外源物质的解毒作用。在许多人类癌症中，PI类GST(GSTP1-1)过表达，并通过结合化疗药物而导致多药耐药。此外，GSTP1-1通过与c-jun NH(2)-末端激酶相互作用而显示出抗凋亡活性，c-jun NH(2)-末端是细胞凋亡的关键调节因子。因此，GSTP1-1被认为是一个有希望的药物治疗靶点。最近，一种有效的GSTs抑制剂6-(7-nitro-2，1，3-benzoxadiazol-4-ylthio)hexanol(NBDHEX)被发现，并在几种具有高抗增殖活性的肿瘤细胞系上进行了测试。为了建立NBDHEX活性的结构基础，我们测定了NBDHEX与GSTP1-1或GSTM2-2(Mu类)结合的晶体结构。NBDHEX在两种情况下都与H-位点结合，但占据不同的位置。此外，该化合物还与GSTM2-2晶体中的GSH硫共价结合，形成Sigma络合物，尽管它在GSTP1-1晶体中是结合的，但不是共轭的。这两种同工酶的H位的几个差异决定了NBDHEX对GSTM2-2的亲和力高于GSTP1-1。一个这样的区别是在GSTP1-1中靠近结合的NBDHEX的ILE(104)的存在，而相应的位置被GSTM2-2中的丙氨酸占据。Ile(104)突变为Valine是一种常见的GSTP1-1多态，我们在这里表明Ile(104)Val和Ile(104)Ala变体对该化合物的亲和力提高了4倍。值得注意的是，在与NBDHEX的配合物中，GSTP1-1/Ile(104)Ala结构显示出化合物在H位内发生了相当大的位移。这些数据可能有助于开发新的抗癌化合物。[癌症资源2009；69(20)：8025-34]
Glutathione S-transferases (GST) constitute a superfamily of enzymes with diversified functions including detoxification from xenobiotics. In many human cancers, Pi class GST (GSTP1-1) is overexpressed and contributes to multidrug resistance by conjugating chemotherapeutics. In addition, GSTP1-1 displays antiapoptotic activity by interacting with c-Jun NH(2)-terminal kinase, a key regulator of apoptosis. Therefore, GSTP1-1 is considered a promising target for pharmaceutical treatment. Recently, a potent inhibitor of GSTs, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), was identified and tested on several tumor cell lines demonstrating high antiproliferative activity. To establish the structural basis of NBDHEX activity, we determined the crystal structure of NBDHEX bound to either GSTP1-1 or GSTM2-2 (mu class). NBDHEX in both cases binds to the H-site but occupies different positions. Furthermore, the compound is covalently attached to the GSH sulfur in the GSTM2-2 crystal, forming a sigma-complex, although it is bound but not conjugated in the GSTP1-1 crystal. Several differences in the H-sites of the two isozymes determine the higher affinity of NBDHEX for GSTM2-2 with respect to GSTP1-1. One such difference is the presence of Ile(104) in GSTP1-1 close to the bound NBDHEX, whereas the corresponding position is occupied by an alanine in GSTM2-2. Mutation of Ile(104) into valine is a frequent GSTP1-1 polymorphism and we show here that the Ile(104)Val and Ile(104)Ala variants display a 4-fold higher affinity for the compound. Remarkably, the GSTP1-1/Ile(104)Ala structure in complex with NBDHEX shows a considerable shift of the compound inside the H-site. These data might be useful for the development of new anticancer compounds. [Cancer Res 2009;69(20):8025-34]