Structural and molecular basis of interaction of HCV non-structural protein 5A with human casein kinase 1α and PKR.
Structural and molecular basis of interaction of HCV non-structural protein 5A with human casein kinase 1α and PKR.
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DOI：
10.1186/1472-6807-12-28
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发表时间：
2012-11-13
影响因子：
--
通讯作者：
Srinivasan N
中科院分区：
文献类型：
--
作者：
Sudha G;Yamunadevi S;Tyagi N;Das S;Srinivasan N
丙型肝炎病毒非结构蛋白5A(NS5A)与人酪蛋白激酶1α(CK1α)和蛋白激酶R(PKR)的相互作用分别具有调节病毒复制和逃避干扰素诱导的免疫应答等不同的功能意义。了解病毒蛋白与两种不同的人类激酶相互作用的结构和分子基础，有助于制定治疗丙型肝炎病毒的策略。已知NS5A的丝氨酸232被人CK1α磷酸化。利用已知的激酶-多肽复合体的三维结构，建立了一个结合CK1α的含有磷酸受体残基丝氨酸232的NS5A多肽的结构模型。从该模型中已经确定了CK1α中的底物相互作用残基，这些残基在CK1家族中被很好地保守。CK1α-底物多肽复合体也被用来理解CK1α与其另一种病毒应激诱导底物--具有晶体结构的肿瘤抑制因子P53反式激活结构域--之间的结构基础。NS5A与另一种人类激酶PKR的相互作用主要是基因特异性的。基因1b的NS5A可以相互作用并抑制PKR，而基因2a/3a的NS5A不能有效地结合和抑制PKR。这是不同基因型别的丙型肝炎患者对干扰素治疗反应不同的主要原因之一。利用PKR晶体结构、序列比对和进化轨迹分析，确定了NS5A 1b与PKR相互作用的一些关键残基。用激酶-底物多肽结构模型鉴定了KK1α的底物相互作用残基。利用PKR晶体结构、NS5A序列分析以及已知的实验结果，预测了PKR与NS5A 1b残基的相互作用。进化轨迹分析结果也支持了不同基因NS5A的干扰素敏感性决定区和可变区3与PKR相互作用的功能意义和本质。设计阻止这种相互作用的抑制剂可以使丙型肝炎病毒1型感染患者对干扰素治疗有良好的反应。
Interaction of non-structural protein 5A (NS5A) of Hepatitis C virus (HCV) with human kinases namely, casein kinase 1α (ck1α) and protein kinase R (PKR) have different functional implications such as regulation of viral replication and evasion of interferon induced immune response respectively. Understanding the structural and molecular basis of interactions of the viral protein with two different human kinases can be useful in developing strategies for treatment against HCV. Serine 232 of NS5A is known to be phosphorylated by human ck1α. A structural model of NS5A peptide containing phosphoacceptor residue Serine 232 bound to ck1α has been generated using the known 3-D structures of kinase-peptide complexes. The substrate interacting residues in ck1α has been identified from the model and these are found to be conserved well in the ck1 family. ck1α – substrate peptide complex has also been used to understand the structural basis of association between ck1α and its other viral stress induced substrate, tumour suppressor p53 transactivation domain which has a crystal structure available. Interaction of NS5A with another human kinase PKR is primarily genotype specific. NS5A from genotype 1b has been shown to interact and inhibit PKR whereas NS5A from genotype 2a/3a are unable to bind and inhibit PKR efficiently. This is one of the main reasons for the varied response to interferon therapy in HCV patients across different genotypes. Using PKR crystal structure, sequence alignment and evolutionary trace analysis some of the critical residues responsible for the interaction of NS5A 1b with PKR have been identified. The substrate interacting residues in ck1α have been identified using the structural model of kinase - substrate peptide. The PKR interacting NS5A 1b residues have also been predicted using PKR crystal structure, NS5A sequence analysis along with known experimental results. Functional significance and nature of interaction of interferon sensitivity determining region and variable region 3 of NS5A in different genotypes with PKR which was experimentally shown are also supported by the findings of evolutionary trace analysis. Designing inhibitors to prevent this interaction could enable the HCV genotype 1 infected patients respond well to interferon therapy.
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影响因子：
3.7
作者：
Cannon, Nathan A.;Donlin, Maureen J.;Tavis, John E.
通讯作者：
Tavis, John E.
EUHCVDB：欧洲丙型肝炎病毒数据库。
影响因子：
14.9
作者：
Combet, Christophe;Garnier, Nicolas;Charavay, Celine;Grando, Delphine;Crisan, Daniel;Lopez, Julien;Dehne-Garcia, Alexandre;Geourjon, Christophe;Bettler, Emmanuel;Hulo, Chantal;Le Mercier, Philippe;Bartenschlager, Ralf;Diepolder, Helmut;Moradpour, Darius;Pawlotsky, Jean-Michel;Rice, Charles M;Trepo, Christian;Penin, Francois;Deleage, Gilbert
通讯作者：
Deleage, Gilbert
影响因子：
8
作者：
Keskin, O;Tsai, CJ;Nussinov, R
通讯作者：
Nussinov, R
影响因子：
64.8
作者：
CHOTHIA, C
通讯作者：
CHOTHIA, C
DOI：
10.1111/j.1432-1033.1988.tb13917.x
发表时间：
1988-03-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BLUNDELL, T;CARNEY, D;SUTCLIFFE, M
通讯作者：
SUTCLIFFE, M