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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design.
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Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design.

机译：人T细胞白血病病毒蛋白酶的晶体结构，一种抗癌药物设计的新靶标。

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摘要

The successful development of a number of HIV-1 protease (PR) inhibitors for the treatment of AIDS has validated the utilization of retroviral PRs as drug targets and necessitated their detailed structural study. Here we report the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substrate-based inhibitor bound in subsites P5 through P5'. Although HTLV-1 PR exhibits an overall fold similar to other retroviral PRs, significant structural differences are present in several loop areas, which include the functionally important flaps, previously considered to be structurally highly conserved. Potential key residues responsible for the resistance of HTLV-1 PR to anti-HIV drugs are identified. We expect that the knowledge accumulated during the development of anti-HIV drugs, particularly in overcoming drug resistance, will help in designing a novel class of antileukemia drugs targeting HTLV-1 PR and in predicting their drug-resistance profile. The structure presented here can beused as a starting point for the development of such anticancer therapies.
机译：大量用于治疗艾滋病的HIV-1蛋白酶（PR）抑制剂的成功开发验证了逆转录病毒PRs作为药物靶标的利用，因此需要对其进行详细的结构研究。在这里，我们报告人类T细胞白血病病毒1型（HTLV-1）PR与底物抑制剂结合在P5至P5'亚位的复合物的结构。尽管HTLV-1 PR的折叠程度与其他逆转录病毒PR相似，但在多个环区域存在明显的结构差异，其中包括功能上重要的襟翼，以前被认为在结构上高度保守。鉴定出负责HTLV-1 PR对抗HIV药物耐药的潜在关键残基。我们希望在抗HIV药物开发过程中积累的知识，特别是在克服耐药性方面，将有助于设计针对HTLV-1 PR的新型抗白血病药物，并预测其耐药性。这里介绍的结构可以用作开发此类抗癌疗法的起点。

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