CiTCoM, CNRS, UMR 8038, Université de Paris, 4 Avenue de L'Observatoire, Paris, 75270, France.
LCBPT, CNRS, UMR 8601, Université de Paris, Paris, 45 Rue des Saints Pères, 75270, France.
Eur J Med Chem. 2020 Oct 15;204:112634. doi: 10.1016/j.ejmech.2020.112634. Epub 2020 Jul 18.
During the maturation of HIV-1 particle, the Gag polyprotein is cleaved into several proteins by the HIV-1 protease. These proteins rearrange to form infectious virus particles. In this study, the solution structure and dynamics of a monomeric mutated domain encompassing the C-terminal of capsid, the spacer peptide SP1 and the nucleocapsid from Gag was characterized by Nuclear Magnetic Resonance in the presence of maturation inhibitor EP39, a more hydro-soluble derivative of BVM. We show that the binding of EP39 decreases the dynamics of CA-SP1 junction, especially the QVT motif in SP1, and perturbs the natural coil-helix equilibrium on both sides of the SP1 domain by stabilizing the transient alpha helical structure. Our results provide new insight into the structure and dynamics of the SP1 domain and how HIV-1 maturation inhibitors interfere with this domain. They offer additional clues for the development of new second generation inhibitors targeting HIV-1 maturation.
在 HIV-1 颗粒成熟过程中，Gag 多聚蛋白被 HIV-1 蛋白酶切割成几种蛋白。这些蛋白重排形成感染性病毒颗粒。在这项研究中，通过核磁共振技术，在成熟抑制剂 EP39（BVM 的一种更亲水的衍生物）存在的情况下，对包含衣壳蛋白 C 端、间隔肽 SP1 和核衣壳的单体突变结构域的结构和动力学进行了研究。我们发现，EP39 的结合降低了 CA-SP1 连接的动力学，特别是 SP1 中的 QVT 基序，并通过稳定瞬态α螺旋结构扰乱了 SP1 结构域两侧的自然螺旋-卷曲平衡。我们的结果为 SP1 结构域的结构和动力学以及 HIV-1 成熟抑制剂如何干扰该结构域提供了新的见解。它们为开发针对 HIV-1 成熟的新一代抑制剂提供了额外的线索。
