| dc.description.abstract | JAK3 is a receptor-associated tyrosine kinase that functions as a key signal transducer within the JAK-STAT cellular signaling pathway to facilitate the production, proliferation, and differentiation of various cell types. Mutations to JAK3 have been shown to disrupt hematopoietic stem cell signaling, causing abnormalities in immune cell production, linking the protein to various immune-deficiency diseases, inflammatory disorders, and cancers. In this study we provide key information about JAK3 structure that gives crucial insight into the function of the protein at the molecular level, allowing for better understanding of the protein’s integral role in cell signaling pathways and immune related disorders. We report two full, theoretical 3D structural models of the JAK3 human protein, encompassing all 7 Jak Homology (JH) protein domains. The kinase domain (JH1), was obtained from the protein data bank (PDBID: 4QPS), while the remaining JH domains were constructed using multi-template homology modeling techniques and molecular dynamics simulations. Sequence alignment revealed conserved homology properties and JAK2 and TYK2 were used as structural templates to model the pseudokinase (JH2) and SH2-FERM (JH3-JH7) domains in JAK3 respectively. Molecular dynamics simulations served to optimize and merge domain models in phases, one domain at a time by two different pathways, validating the models at each phase using RMSD and energy minimization calculations. The structural and dynamic properties of the protein, including residue interactions, domain-domain modulations, and conformational behavior are quantified. This study is an important step in better understanding JAK3 structure-function mechanisms and molecular interactions and may aid in discovery of novel inhibitors with higher JAK3 selectivity through structure-based drug design. | en |
