Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

SRC homology 2 (SH2)-containing inositol 5′-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], important for insulin signaling, makes it an important target against type 2 diabetes. The insulin-induced SHIP2 interaction with Shc is very important for the membrane localization and functioning of SHIP2. There is a bidentate relationship between the two proteins where two domains each from SHIP2 and Shc are involved in mutual binding. However in the present study, the SHIP2-SH2 domain binding with the phosphorylated tyrosine 317 on the collagen-homology (CH) domain of Shc, has been studied due to the indispensability of this interaction in SHIP2 localization. In the absence of the crystal structure of SHIP2-SH2, its structural model was developed followed by tracking its molecular interactions with Shc through molecular docking and dynamics studies. This study revealed much about the structural interactions between the SHIP2-SH2 and Shc-CH. Finally, docking study of a nonpeptide inhibitor into the SHIP2-SH2 domain further confirmed the structural interactions involved in ligand binding and also proposed the inhibitor as a major starting point against SHIP2-SH2 inhibition. The insights gained from the current study should prove useful in the design of more potent inhibitors against type 2 diabetes

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease