The 1.8 Å Crystal Structure of ACTIBIND Suggests a Mode of Action for T2 Ribonucleases As Antitumorigenic Agents
The 1.8 Å Crystal Structure of ACTIBIND Suggests a Mode of Action for T2 Ribonucleases As Antitumorigenic Agents
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DOI：
10.1021/jm1015507
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发表时间：
2012-02-09
影响因子：
7.3
通讯作者：
Almog, Orna
中科院分区：
文献类型：
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作者：
de Leeuw, Marina;Gonzalez, Ana;Almog, Orna
ACTIBIND及其人类同源物RNASET2是T2核糖核酸酶(RNase)。核糖核酸酶是一种普遍存在的高效酶，它能将RNA水解为3‘端单核苷酸，并具有抗肿瘤和抗血管生成活性。此前，我们已经证明ACTIBIND和RNASET2结合肌动蛋白并干扰细胞骨架网络结构，从而抑制癌细胞和血管内皮细胞的运动和侵袭性。我们还发现ACTIBIND与肌动蛋白的结合摩尔比为1：2。在这里，我们进一步表征了ACTIBIND，并测定了其1.8埃分辨率的晶体结构，这使得我们能够提出两个与肌动蛋白产生结合位点的结构元素。我们认为每个结合位点都由一个半胱氨酸残基和一个保守的氨基酸组成。这些结合位点可能干扰细胞骨架网络结构，从而可能与ACTIBIND及其人类类似物RNASET2的抗肿瘤和抗血管生成活性有关。
ACTIBIND and its human homologue RNASET2 are T2 ribonucleases (RNases). RNases are ubiquitous and efficient enzymes that hydrolyze RNA to 3' mononucleotides and also possess antitumorigenic and antiangiogenic activities. Previously, we have shown that ACTIBIND and RNASET2 bind actin and interfere with the cytoskeletal network structure, thereby inhibiting cell motility and invasiveness in cancer and in endothelial cells. We also showed that ACTIBIND binds actin in a molar ratio of 1:2. Here, we further characterize ACTIBIND and determine its crystal structure at 1.8 angstrom resolution, which enables us to propose two structural elements that create binding sites to actin. We suggest that each of these binding sites is composed of one cysteine residue and one conserved amino acid region. These binding sites possibly interfere with the cytoskeleton network structure and as such may be responsible for the antitumorigenic and antiangiogenic activities of ACTIBIND and its human analogue RNASET2.