RESUMO
The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies reveal that the Omicron BA.2 spike trimer have 11-fold and 2-fold higher potency to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to have efficient inhibition of Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants from human-cat-mouse-human circle, which could have important implications in establishing an effective strategy in combating viral infection.
RESUMO
The Omicron variant of SARS-CoV-2 has rapidly become the dominant infective strain and the focus efforts against the ongoing COVID-19 pandemic. Here we report an extensive set of structures of the Omicron spike trimer by its own or in complex with ACE2 and an anti-Omicron antibody. These structures reveal that most Omicron mutations are located on the surface of the spike protein, which confer stronger ACE2 binding by nearly 10 folds but become inactive epitopes resistant to many therapeutic antibodies. Importantly, both RBD and the closed conformation of the Omicron spike trimer are thermodynamically unstable, with the melting temperature of the Omicron RBD decreased by as much as 7{degrees}C, making the spiker trimer prone to random open conformations. An unusual RBD-RBD interaction in the ACE2-spike complex unique to Omicron is observed to support the open conformation and ACE2 binding, serving the basis for the higher infectivity of Omicron. A broad-spectrum therapeutic antibody JMB2002, which has completed Phase 1 clinical trial, is found to interact with the same two RBDs to inhibit ACE2 binding, in a mode that is distinguished from all previous antibodies, thus providing the structural basis for the potent inhibition of Omicron by this antibody. Together with biochemical data, our structures provide crucial insights into higher infectivity, antibody evasion and inhibition of Omicron.
RESUMO
KDM5B is a histone H3K4me2/3 demethylase. The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear. In this paper, we observed that PHD1KDM5B interacts with unmethylated H3K4me0. Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers. The disruption of this interaction by double mutations on the residues in the interface (L325A/D328A) decreases the H3K4me2/3 demethylation activity of KDM5B in cells by approximately 50% and increases the transcriptional repression of tumor suppressor genes by approximately twofold. These findings imply that PHD1KDM5B may help maintain KDM5B at target genes to mediate the demethylation activities of KDM5B.
Assuntos
Humanos , Sítios de Ligação , Genética , Cristalografia por Raios X , Regulação da Expressão Gênica , Células HEK293 , Histonas , Química , Metabolismo , Histona Desmetilases com o Domínio Jumonji , Química , Genética , Metabolismo , Lisina , Química , Metabolismo , Espectroscopia de Ressonância Magnética , Metilação , Microscopia de Fluorescência , Modelos Moleculares , Mutação , Proteínas Nucleares , Química , Genética , Metabolismo , Peptídeos , Química , Genética , Metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Repressoras , Química , Genética , MetabolismoRESUMO
Objective To explore the impact of nursing intervention on quality of life of blood dialysis patients.Methods 60 cases of hemodialysis patients were selected and divided into the experimental group and the control group with 30 patients in each group.The control group was given conventional nursing,while the experimental group was given systematic health education and psychological nursing.The differences in life quality before and after the intervention in the experimental group was evaluated with self-designed questionnaire.The changes in motor function,psychological function,social function,and material life were compared before and after the intervention between two groups.Results After the intervention,the score of motor function,psychological function and total evaluation of the experimental group were higher than those of the control group.Conclusions Nursing intervention can effectively alleviate the discomfort feeling of patients,reduce their mental pressure,increase their quality of life.Nursing intervention is closely related with quality of life.
