Atomic-resolution structure of HIV-1 capsid tubes by magic-angle spinning NMR
Atomic-resolution structure of HIV-1 capsid tubes by magic-angle spinning NMR
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DOI：
10.1038/s41594-020-0489-2
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发表时间：
2020-09-01
影响因子：
16.8
通讯作者：
Polenova, Tatyana
中科院分区：
文献类型：
--
作者：
Lu, Manman;Russell, Ryan W.;Polenova, Tatyana
HIV-1衣壳在病毒复制中起着多种关键作用，抑制衣壳组装是治疗干预的一个有吸引力的靶点。在这里，我们报告的原子分辨率结构的衣壳蛋白（CA）管，确定魔角旋转NMR和数据引导的分子动力学模拟。功能上重要的区域，包括NTD β-发夹、亲环素A结合环、六聚体中心孔中的残基和NTD-CTD接头区域，都得到了很好的定义。个别CA链的结构，它们在管的伪六聚体单元中的排列和六聚体间界面与完整衣壳中的那些一致，并且与以扁平六聚体为特征的晶体结构中的组织基本上不同。CA管中的固有曲率由接头区域中的残基以及二聚体和三聚体界面的构象可变性控制。本文的结构揭示了HIV-1衣壳蛋白（CA）在原子水平上的结构细节，为新型衣壳蛋白抑制剂的设计提供了重要的指导。
HIV-1 capsid plays multiple key roles in viral replication, and inhibition of capsid assembly is an attractive target for therapeutic intervention. Here, we report the atomic-resolution structure of capsid protein (CA) tubes, determined by magic-angle spinning NMR and data-guided molecular dynamics simulations. Functionally important regions, including the NTD beta-hairpin, the cyclophilin A-binding loop, residues in the hexamer central pore, and the NTD-CTD linker region, are well defined. The structure of individual CA chains, their arrangement in the pseudo-hexameric units of the tube and the inter-hexamer interfaces are consistent with those in intact capsids and substantially different from the organization in crystal structures, which feature flat hexamers. The inherent curvature in the CA tubes is controlled by conformational variability of residues in the linker region and of dimer and trimer interfaces. The present structure reveals atomic-level detail in capsid architecture and provides important guidance for the design of novel capsid inhibitors.Structures of HIV-1 capsid protein (CA) in tubular assemblies, determined by MAS-NMR, reveal the basis of CA's conformational plasticity.