Abstract
In this work, we study the dynamics and the energetics of the all-atom structure of a neuronal-specific serine/threonine kinase c-Jun N-terminal kinase 3 (JNK3) in three states: unphosphorylated, phosphorylated, and ATP-bound phosphorylated. A series of 2 µs atomistic simulations followed by a conformational landscape mapping and a principal component analysis supports the mechanistic understanding of the JNK3 inactivation/activation process and also indicates key structural intermediates. Our analysis reveals that the unphosphorylated JNK3 undergoes the ‘open-to-closed’ movement via a two-step mechanism. Furthermore, the phosphorylation and ATP-binding allow the JNK3 kinase to attain a fully active conformation. JNK3 is a widely studied target for small-drugs used to treat a variety of neurological disorders. We believe that the mechanistic understanding of the large-conformational changes upon the activation of JNK3 will aid the development of novel targeted therapeutics.
Highlights
Understanding of the conformational dynamics of kinases has been an area of tremendous interests in the last ten years[1,2,3,4,5,6]
The modeled structure served as a starting point to generate the apo and ATP-bound structures
The majority of the drug discovery efforts for Jun NH2-terminal kinase 3 (JNK3) have been directed towards targeting the ATP-binding site and inhibition of the interaction with the scaffold protein JIP1
Summary
Understanding of the conformational dynamics of kinases has been an area of tremendous interests in the last ten years[1,2,3,4,5,6]. The atomistic simulations have helped to design several kinase inhibitors by unraveling the conformational rearrangements of the protein[7,8,9,10,11]. We have studied the structural dynamics of the kinase known as c-Jun NH2-terminal kinase 3 (JNK3). JNKs are serine/threonine kinases belonging to the evolutionary conserved mitogen-activated protein kinase (MAPK) family. JNKs are known as stress-activated protein kinases because of their activation by extracellular stress stimuli and several cytokines. Dual phosphorylation of threonine and tyrosine residues of the conserved Thr-Pro-Tyr (TPY) motif (at the phosphorylation lip, known as activation loop or A-loop) by the specific kinases MKK4 and MKK7 activates JNKs12,14. Activated JNKs phosphorylate several nuclear and non-nuclear substrates such as c-Jun, ATF-2, Elk-1, the mitochondrial Bcl[2] protein family, and others[26,27]. Little experimental evidence is available which can explain the underlying regulatory mechanism of JNK3 (or JNKs) in unphosphorylated and phosphorylated states
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