The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites.
The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites.
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DOI：
10.1017/s0031182014000857
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发表时间：
2014-09
期刊：
影响因子：
2.4
通讯作者：
Ojo KK
中科院分区：
文献类型：
--
作者：
Keyloun KR;Reid MC;Choi R;Song Y;Fox AMW;Hillesland HK;Zhang Z;Vidadala R;Merritt EA;Lau AOT;Maly DJ;Fan E;Barrett LK;Van Voorhis WC;Ojo KK
个体CDPKs的具体作用各不相同，但总的来说，它们调节着寄生虫生存所必需的基本生物学功能。通过对333种BKIs的筛选，比较分析了犬新孢子虫、柔嫩艾美耳球虫和牛巴贝斯钙依赖蛋白激酶(CDPKs)与恶性疟原虫、微小隐孢子虫和弓形虫的构效关系(SAR)。结构建模和实验数据表明，除了看门人之外的残基影响化合物-蛋白质的相互作用，从而产生不同的敏感性图谱。随后，我们确定了在开发广谱apicplexan CDPK抑制剂时所需的每个同源物的ATP结合空腔内潜在的氨基酸结构影响。尽管BKI文库是针对甘氨酸守门人CDPKs的特异性抑制和苏氨酸守门人SRC激酶的低抑制率而开发的，但一些文库化合物对含有丝氨酸或苏氨酸的CDPKs具有活性。CDPK同系物对BKI的敏感性差异可以根据疏水口袋的大小和方向的不同以及ATP结合腔内其他氨基酸位置的特异性变异来解释。特别是，BbCDPK4和PfCDPK1对比EtCDPK1更大比例的化合物敏感，尽管这三个CDPKs中都存在苏氨酸守门人。
Specific roles of individual CDPKs vary, but in general, they mediate essential biological functions necessary for parasite's survival. A comparative analysis of the structural-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis Calcium-dependent Protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum, and Toxoplasma gondii was performed by screening against 333 Bumped kinase inhibitors (BKIs). Structural modeling and experimental data revealed that residues other than the gatekeeper influence compound-protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase; some library compounds exhibit activity against serine or threonine containing CDPKs. Divergent BKI sensitivity of CDPK homologs could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of threonine gatekeeper in all the three CDPKs.