Computational and Experimental Studies on Human Misshapen / NIK- Related Kinase MINK-1

We have studied the structure and function of Human Misshapen / NIK-related kinase (MINK-1)through a combination of computational methods and experimental approaches,including (1)fold recognition and sequence-structure alignment for each structural domain using the threading program PROSPECT,(2)gene expression and protein-protein interaction analysis of yeast homologs of human MINK-1 domains,and (3)yeast two-hybrid screening for proteins that interact with human MINK-1.Our structure prediction dissects MINK-1 into four domains:a conserved N-terminal kinase domain,followed by a coiled-coil region and a proline-rich region,and a C- terminal GCK domain.Gene expression and yeast two-hybrid analysis of yeast homologs of the MINK-1 domains suggest that MINK-1 may be involved in cell-cycle progression and cytoskeletal control.Consistent with these predicted functions,our in-house yeast two-hybrid screen for proteins that interact with human MINK-1 provides strong evidence that the coiled-coil and proline-rich domains of MINK-1 participate in the regulation of cytoskeletal organization,cell-cycle control and apoptosis.A homology model of the MINK-1 kinase domain was used to screen the NCI open compound database in DOCK,and chemical compounds with pharmaceutically acceptable properties were identified.Further medicinal chemistry compound structure optimization and kinase assays are underway.