Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases.
Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases.
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DOI：
10.1099/vir.0.82704-0
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发表时间：
2007-07
期刊：
影响因子：
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通讯作者：
Tamás Sperka;Gabriella Miklóssy;Y. Tie;P. Bagossi;G. Zahuczky;P. Boross;Krisztina Matúz;R. Harrison;I. Weber;J. Tözsér
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文献类型：
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作者：
Tamás Sperka;Gabriella Miklóssy;Y. Tie;P. Bagossi;G. Zahuczky;P. Boross;Krisztina Matúz;R. Harrison;I. Weber;J. Tözsér
牛白血病病毒 (BLV) 是了解人类 T 淋巴细胞病毒 1 (HTLV-1) 的有价值的模型系统；传染性 BLV 克隆的可用性以及动物模型系统将有助于探索抗 HTLV-1 策略。然而，BLV 蛋白酶 (PR) 的特异性和抑制剂敏感性尚未得到详细表征。为了促进此类研究，建立了该酶的分子模型。使用代表各种逆转录病毒中天然存在的切割位点的一组寡肽研究了 BLV PR 的特异性。与 HTLV-1 PR 不同，但与人类免疫缺陷病毒 1 (HIV-1) 酶相似，BLV PR 能够水解大多数肽，大部分位于与其各自宿主 PR 相同的位置，表明其具有广泛的特异性。当 BLV PR 底物结合位点的氨基酸残基被 HIV-1 PR 的等效氨基酸残基取代时，许多取代导致蛋白质失活，表明对突变非常敏感，正如之前在 HTLV-1 PR 中观察到的那样。通过使用一系列在代表天然存在的 HTLV-1 PR 切割位点的序列中含有氨基酸取代的肽，进一步研究了该酶的特异性。此外，还在 BLV PR 上测试了 HIV-1 PR、HTLV-1 PR 和其他逆转录病毒蛋白酶的抑制剂。有趣的是，BLV PR 比 HTLV-1 PR 对所测试的抑制剂更敏感。因此，尽管存在特异性差异，但就 PR 的突变不耐受性和抑制剂敏感性而言，BLV 和相应的动物模型系统可能为测试针对 HTLV-1 的 PR 抑制剂提供良好的模型。
Bovine leukemia virus (BLV) is a valuable model system for understanding human T-lymphotropic virus 1 (HTLV-1); the availability of an infectious BLV clone, together with animal-model systems, will help to explore anti-HTLV-1 strategies. Nevertheless, the specificity and inhibitor sensitivity of the BLV protease (PR) have not been characterized in detail. To facilitate such studies, a molecular model for the enzyme was built. The specificity of the BLV PR was studied with a set of oligopeptides representing naturally occurring cleavage sites in various retroviruses. Unlike HTLV-1 PR, but similar to the human immunodeficiency virus 1 (HIV-1) enzyme, BLV PR was able to hydrolyse the majority of the peptides, mostly at the same position as did their respective host PRs, indicating a broad specificity. When amino acid residues of the BLV PR substrate-binding sites were replaced by equivalent ones of the HIV-1 PR, many substitutions resulted in inactive protein, indicating a great sensitivity to mutations, as observed previously for the HTLV-1 PR. The specificity of the enzyme was studied further by using a series of peptides containing amino acid substitutions in a sequence representing a naturally occurring HTLV-1 PR cleavage site. Also, inhibitors of HIV-1 PR, HTLV-1 PR and other retroviral proteases were tested on the BLV PR. Interestingly, the BLV PR was more susceptible than the HTLV-1 PR to the inhibitors tested. Therefore, despite the specificity differences, in terms of mutation intolerance and inhibitor susceptibility of the PR, BLV and the corresponding animal-model systems may provide good models for testing of PR inhibitors that target HTLV-1.