RESUMO
The HIV-1 envelope glycoprotein (Env) plays crucial role in viral infection by facilitating viral attachment to host cells and inducing fusion of the virus with the host cell membrane. This fusion allows the HIV-1 viral genome to enter the target cell then triggering various stages of the viral life cycle. The native Env directly interacts with the main receptor CD4 and the co-receptor (CCR5 or CXCR4) in human cell membrane then induces membrane fusion. The elucidation of the structure of Env with CD4 and co-receptors in different HIV-1 subtypes is essential for the understanding of the mechanism of virus entry. Here we report the Cryo-EM structure of the CD4-bound HIV-1 heterotrimeric Env from Asia prevalent CRF07_BC CH119 strain. In this structure, the binding of three CD4 molecules with Env induced extensively conformational changes in gp120, resulting in the transformation of the Env from close state to intermediate open state. Additionally, the conformational shift of V1/V2 loops of the heterotrimeric Env allosterically expose the V3 loop and promoting the further interactions with co-receptor CCR5 or CXCR4. These findings not only illustrate the structural complexity and plasticity of HIV-1 Env but also give new insights how the biological trimeric Env initialize the immune recognition and membrane fusion.
Assuntos
Antígenos CD4 , Proteína gp120 do Envelope de HIV , HIV-1 , HIV-1/metabolismo , Humanos , Antígenos CD4/metabolismo , Antígenos CD4/química , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/genética , Microscopia Crioeletrônica , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Receptores CCR5/metabolismo , Receptores CCR5/química , Ligação Proteica , Modelos Moleculares , Conformação Proteica , Infecções por HIV/virologia , Infecções por HIV/metabolismo , Multimerização Proteica , Receptores CXCR4/metabolismo , Receptores CXCR4/química , ÁsiaRESUMO
Different valence states of copper (Cu) ions are involved in complicated redox reactions in vivo, which are closely related to tumor proliferation and death pathways, such as cuproptosis and chemodynamic therapy (CDT). Cu ion mediated Fenton-like reagents induced tumor cell death which presents compelling attention for the CDT of tumors. However, the superiority of different valence states of Cu ions in the antitumor effect is unknown. In this study, we investigated different valence states of Cu ions in modulating tumor cell death by Cu-chelated cyanine dye against triple-negative breast cancer. The cuprous ion (Cu+) and copper ion (Cu2+) were chelated with four nitrogen atoms of dipicolylethylenediamine-modified cyanine for the construction of Cu+ and Cu2+ chelated cyanine dyes (denoted as CC1 and CC2, respectively). Upon 660 nm laser irradiation, the CC1 or CC2 can generate reactive oxygen species, which could disrupt the cyanine structure, achieving the rapid release of Cu ions and initiating the Fenton-like reaction for CDT. Compared with Cu2+-based Fenton-like reagent, the CC1 with Cu+ exhibited a better therapeutic outcome for the tumor due to there being no need for a reduction by glutathione and a shorter route to generate more hydroxyl radicals. Our findings suggest the precision delivery of Cu+ could achieve highly efficient antitumor therapy.
