Crystal structures of murine angiogenin-2 and -3-probing 'structure--function' relationships amongst angiogenin homologues.
Crystal structures of murine angiogenin-2 and -3-probing 'structure--function' relationships amongst angiogenin homologues.
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DOI：
10.1111/febs.12071
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Acharya KR
中科院分区：
文献类型：
--
作者：
Iyer S;Holloway DE;Acharya KR
血管生成素（Angiogenin, Ang）是一种有效的新生血管诱导剂。人类Ang的点突变与癌症进展和两种神经退行性疾病：肌萎缩性侧索硬化症和帕金森病有关。对Ang进行深入的结构和功能分析对于确定牛胰腺rna酶a的新同源物的功能至关重要。然而，由于活性位点难以接近，与结晶Ang的抑制剂结合研究（用于设计潜在的抗癌药物）一直受到阻碍。用Ang的小鼠同源物进行的实验不仅克服了研究人类蛋白质在健康个体中的作用时遇到的明显的实际限制，而且小鼠血管生成素（mAng和mAng-4）的晶体结构也显示出它们在活性位点的小分子抑制剂结合的可视化方面具有更大的潜力。在本研究中，我们分别以1.6和1.8 Å分辨率报道了另外两种小鼠Ang同源物，莽2和莽3的晶体结构。这些构成了活性位点有锌离子结合的Ang的第一个晶体结构，并为这些二价阳离子抑制酶的核糖核分解活性的可能模式提供了一些见解。这两种结构都表明，形成假定的P1、B1和B2亚位的残基占据的位置与人类Ang中的对应位置相似，可能具有保守的作用。然而，mAng-3中c末端的不太突出的构象和mAng-2的B1亚位中硫酸盐离子的存在表明，这些蛋白质具有用于抑制剂结合研究的潜力。我们还讨论了不同的Ang同源物之间的结构相似性和差异性的生物学相关性。mAng-2 （3ZBV）和mAng-3 （3ZBW）的原子坐标和结构因子已存储在美国新泽西州新不伦瑞克罗格斯大学结构生物信息学研究合作实验室蛋白质数据库中（http://www.rcsb.org/）。x射线晶体学研究锰2和锰3的结合（查看相互作用）
Angiogenin (Ang) is a potent inducer of neovascularization. Point mutations in human Ang have been linked to cancer progression and two neurodegenerative diseases: amyotrophic lateral sclerosis and Parkinson's disease. Intensive structural and functional analyses of Ang have been paramount in assigning functions to this novel homologue of bovine pancreatic RNase A. However, inhibitor-binding studies with crystalline Ang (for designing potential anti-cancer drugs) have been hampered as a result of the inaccessibility of the active site. Experiments with the murine homologues of Ang have not only overcome the obvious practical limitations encountered when studying the role of a human protein in healthy individuals, but also the crystal structures of murine angiogenins (mAng and mAng-4) have revealed themselves to have greater potential for the visualization of small-molecule inhibitor binding at the active site. In the present study, we report the crystal structures of two more murine Ang paralogues, mAng-2 and mAng-3, at 1.6 and 1.8 Å resolution, respectively. These constitute the first crystal structures of an Ang with a zinc ion bound at the active site and provide some insight into the possible mode of inhibition of the ribonucleolytic activity of the enzyme by these divalent cations. Both structures show that the residues forming the putative P1, B1 and B2 subsites occupy positions similar to their counterparts in human Ang and are likely to have conserved roles. However, a less obtrusive conformation of the C-terminal segment in mAng-3 and the presence of a sulfate ion in the B1 subsite of mAng-2 suggest that these proteins have the potential to be used for inhibitor-binding studies. We also discuss the biological relevance of the structural similarities and differences between the different Ang homologues. The atomic coordinates and structure factors for mAng-2 (3ZBV) and mAng-3 (3ZBW) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ, USA (http://www.rcsb.org/). mAng2 and mAng3 bind by x-ray crystallography (View interaction)
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DOI：
10.1107/s0907444905029616
发表时间：
2005-12
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
通讯作者：
--
影响因子：
1.6
作者：
Holloway, DE;Hares, MC;Acharya, KR
通讯作者：
Acharya, KR
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
DOI：
10.1007/bf01024885
发表时间：
1988-08-01
期刊：
JOURNAL OF PROTEIN CHEMISTRY
影响因子：
--
作者：
HARPER, JW;VALLEE, BL
通讯作者：
VALLEE, BL
影响因子：
2.9
作者：
FETT, JW;STRYDOM, DJ;VALLEE, BL
通讯作者：
VALLEE, BL