Structure of the complex between the HIV-1 nucleocapsid protein NCp7 and the single-stranded pentanucleotide d(ACGCC)
Structure of the complex between the HIV-1 nucleocapsid protein NCp7 and the single-stranded pentanucleotide d(ACGCC)
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DOI：
10.1006/jmbi.1998.2098
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发表时间：
1998-10-23
影响因子：
5.6
通讯作者：
Roques, BP
中科院分区：
文献类型：
--
作者：
Morellet, N;Déméné, H;Roques, BP
HIV-1 Mal的核衣壳蛋白NCp7包含两个连续的CX2CX4HX4C型Zn指节，主要通过单链核酸结合在病毒颗粒形态发生、基因组RNA包装和病毒感染性中发挥重要作用。我们在此报告了通过 H-1 2D NMR 对 (12-53)NCp7（包含两个 Zn 指节）和 d(ACGCC)（对应于最短 NCp7 结合位点的脱氧核苷酸序列类似物）之间形成的复合物进行的研究。 (12-53)NCp7/d(ACGCC) 复合物的十个结构已从 607 个 NOE 衍生距离约束中获得，其中 28 个是分子间距离约束，并且来自分子动力学研究。寡核苷酸几乎垂直于连接两个锌指节的序列。 Trp37吲哚环插入C2和G3碱基之间并堆叠在后者上。该复合物通过疏水相互作用和氢键而稳定，并解释了观察到的由锌指节结构域突变引起的病毒感染性丧失。因此，通过NMR发现d(ACGCC)和失活突变体Cys23(12-53)NCp7之间的相互作用与用野生型肽观察到的完全不同。这些结果提出了 NCp7 在病毒形态发生和复制中的作用机制，这有助于设计通过新机制起作用的可能的抗病毒药物。 (C) 1998 年学术出版社。
The nucleocapsid protein NCp7 of HIV-1 Mal contains two successive Zn knuckles of the CX2CX4HX4C type and plays a major role in virion morphogenesis, genomic RNA packaging and viral infectivity, mainly through single-stranded nucleic acid binding. We report here the study by H-1 2D NMR of the complex formed between the (12-53)NCp7, encompassing the two Zn knuckles, and d(ACGCC), a deoxynucleotide sequence analog corresponding to the shortest NCp7 binding site. Ten structures of the (12-53)NCp7/d(ACGCC) complex have been obtained from 607 NOE-derived distance constraints, 28 of which are intermolecular, and from molecular dynamics studies. The oligonucleotide is almost perpendicular to the sequence linking the two Zn knuckles. The Trp37 indole ring is inserted between the C2 and G3 bases and stacked on the latter. The complex is stabilized by hydrophobic interactions and hydrogen bonds, and accounts for the observed loss of virus infectivity induced by mutations in the Zn knuckle domain. Thus, the interaction between d(ACGCC) and the inactive mutant Cys23 (12-53)NCp7 was found by NMR to be completely different from that observed with the wild-type peptide. A mechanism of action for NCp7 in virus morphogenesis and replication is proposed from these results, which could facilitate the design of possible antiviral agents acting by a new mechanism. (C) 1998 Academic Press.