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The Lys103Asn mutation of HIV-1 RT: A novel mechanism of drug resistance
文献类型：期刊论文
| 作者 | Hsiou, Y; Ding, JP; Das, K; Clark, AD; Boyer, PL; Lewi, P; Janssen, PAJ; Kleim, JP; Rosner, M; Hughes, SH |
| 刊名 | JOURNAL OF MOLECULAR BIOLOGY
 |
| 出版日期 | 2001 |
| 卷号 | 309期号:2页码:437-445 |
| 关键词 | AIDS drug resistance HIV-1 reverse transcriptase non-nucleoside inhibitor X-ray crystallography |
| 通讯作者 | Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA., |
| 英文摘要 | Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are widely used in the treatment of HIV infection. Loviride (an alpha -APA derivative) and HEY 097 (a quinoxaline derivative) are two potent non-nucleoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of drug-resistant mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic pocket that binds NNRTIs. Substitution of asparagine for lysine at position 103 of HIV-1 RT is associated with the development of resistance to NNRTIs; this mutation contributes to clinical failure of treatments employing NNRTIs. We have determined the structures of the unliganded form of the Lys103Asn mutant HIV-1 RT and in complexes with loviride and HEY 097. The structures of wild-type and Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type and Lys103Asn mutant HIV-1 RT structures reveals a network of hydrogen bonds in the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water molecules in the pocket and nearby pocket residues. The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could interfere with the ability of inhibitors to bind to the enzyme. These results are consistent with kinetic data indicating that NNRTIs bind more slowly to Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to different classes of NNRTIs. Design of NNRTIs that make favorable interactions with the Asn103 side-chain should be relatively effective against the Lys103Asn drug-resistant mutant. (C) 2001 Academic Press. |
| 学科主题 | Biochemistry & Molecular Biology |
| 类目[WOS] | Biochemistry & Molecular Biology |
| 关键词[WOS] | HUMAN-IMMUNODEFICIENCY-VIRUS ; TYPE-1 REVERSE-TRANSCRIPTASE ; ANTIBODY FAB FRAGMENT ; DOUBLE-STRANDED DNA ; ANGSTROM RESOLUTION ; NONNUCLEOSIDE INHIBITORS ; CONFORMATIONAL-CHANGES ; CRYSTAL-STRUCTURE ; HBY-097 ; COMPLEX |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000169266700008 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/2602]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Hsiou, Y,Ding, JP,Das, K,et al. The Lys103Asn mutation of HIV-1 RT: A novel mechanism of drug resistance[J]. JOURNAL OF MOLECULAR BIOLOGY,2001,309(2):437-445. |
| APA | Hsiou, Y.,Ding, JP.,Das, K.,Clark, AD.,Boyer, PL.,...&Arnold, E.(2001).The Lys103Asn mutation of HIV-1 RT: A novel mechanism of drug resistance.JOURNAL OF MOLECULAR BIOLOGY,309(2),437-445. |
| MLA | Hsiou, Y,et al."The Lys103Asn mutation of HIV-1 RT: A novel mechanism of drug resistance".JOURNAL OF MOLECULAR BIOLOGY 309.2(2001):437-445. |
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