Computational Design of Druglike Allosteric Inhibitors of AXL and MET Receptor Tyrosine Kinases

Abstract

Dyneins are minus-end microtubule motor proteins which can be grouped into two groups, cytoplasmic and flagellar dyneins. The cytoplasmic dynein is processive, i.e. ''walks'' along the microtubule; while flagellar dynein is involved in oscillatory beating of cilia and flagella. These functional differences led us to study the similarity and dissimilarity of these two dynein proteins in binding to the microtubule. Here, we compare the binding of flagellar and cytoplasmic microtubule binding domain (MTBDs) to microtubule emphasizing on intrinsically disordered regions (IDRs) at the C-terminal of aand b-tubulins. We demonstrate that the interactions between cytoplasmic and flagellar MTBD with E-hooks are different, in terms of residues involvement and number of contacts at various MTBD-microtubule distances. Furthermore, the computational modeling indicates that there is a correlation between number of contacts between MTBD and E-hooks and the RMSF (conformational changes) of the corresponding MTBD.