Computational insights into the active structure of SGK1 and its implication for ligand design

Serum- and glucocorticoid-inducible kinase 1 (SGK1), a protein kinase, shares significant structural similarity with other members of the AGC protein kinase family. It has been reported that the inactive SGK1 structure lacks αC helix and this unique feature makes it distinct from other protein kinases. Activation of SGK1 by PDK1 requires phosphorylation at Thr256, but the structural insights of the activation remain unclear. The co-crystal structures of small molecule inhibitors, Magnesium (Mg+2) and ATP bound to the inactive SGK1 are reported however the important regulatory domains such as αC helix are missing in these crystal structures. We modelled the missing αC domain and employed computational molecular dynamics simulations to study the conformational changes in the WT and phosphorylated human SGK1 to systematically investigate how the individual domain motions are modulated by the binding of substrate and Mg+2. The MD results corroborate with the experiential findings and has shown that the inactive SGK1 lacks αC helix content. Surprisingly, we find that the active SGK1 structure closely resembles with other protein kinases and adopt the αC helix content up on SGK1 phosphorylation. However, the residues participating in αC helix formation are fewer than reported in protein kinase A structure, a close relative of SGK1. The computational binding analysis reveals that most of the SGK1 selective inhibitors have less binding affinity for active SGK1 than some FDA-approved kinase inhibitors such as Afatinib, Tofacitinib, Dabrafenib, and Palbociclib. Only EMD638683 was seen as a strong candidate for selective SGK1 inhibition. To our knowledge, this is the first dynamic study of SGK1 that provides new structural insights around the active site that would surely help the experimental biologists for the design of suitable selective ligands able to inhibit or activate SGK1 function