4CL1

The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors

4CL1 の概要

• エントリーDOI: 10.2210/pdb4cl1/pdb
• 分子名称: NON-STRUCTURAL PROTEIN 5A, ZINC ION, SULFATE ION (3 entities in total)
• 機能のキーワード: viral protein
• 由来する生物種: HEPATITIS C VIRUS (ISOLATE H77)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 79680.25

構造登録者

Lambert, S.M.,Langley, D.R.,Garnett, J.A.,Angell, R.,Hedgethorne, K.,Meanwell, N.A.,Matthews, S.J. (登録日: 2014-01-10, 公開日: 2014-04-02, 最終更新日: 2024-11-20)

主引用文献

Lambert, S.M.,Langley, D.R.,Garnett, J.A.,Angell, R.,Hedgethorne, K.,Meanwell, N.A.,Matthews, S.J.
The Crystal Structure of Ns5A Domain 1 from Genotype 1A Reveals New Clues to the Mechanism of Action for Dimeric Hcv Inhibitors.
Protein Sci., 23:723-, 2014

PubMed Abstract: New direct acting antivirals (DAAs) such as daclatasvir (DCV; BMS-790052), which target NS5A function with picomolar potency, are showing promise in clinical trials. The exact nature of how these compounds have an inhibitory effect on HCV is unknown; however, major resistance mutations appear in the N-terminal region of NS5A that include the amphipathic helix and domain 1. The dimeric symmetry of these compounds suggests that they act on a dimer of NS5A, which is also consistent with the presence of dimers in crystals of NS5A domain 1 from genotype 1b. Genotype 1a HCV is less potently affected by these compounds and resistance mutations have a greater effect than in the 1b genotypes. We have obtained crystals of domain 1 of the important 1a NS5A homologue and intriguingly, our X-ray crystal structure reveals two new dimeric forms of this domain. Furthermore, the high solvent content (75%) makes it ideal for ligand-soaking. Daclatasvir (DCV) shows twofold symmetry suggesting NS5A dimers may be of physiological importance and serve as potential binding sites for DCV. These dimers also allow for new conformations of a NS5A expansive network which could explain its operation on the membranous web. Additionally, sulfates bound in the crystal structure may provide evidence for the previously proposed RNA binding groove, or explain regulation of NS5A domain 2 and 3 function and phosphorylation, by domain 1.

PubMed: 24639329
DOI: 10.1002/PRO.2456

実験手法

X-RAY DIFFRACTION (3.5 Å)