Aberrant JNK signaling can result in two main forms of disease in humans: 1) neurological, coronary, hepatobiliary, and respiratory diseases and 2) autoimmune, inflammatory, and cancer conditions. Enantiomers of the lignan zuonin A, (-)-zuonin A and (+)-zuonin A, have been shown to bind to JNK isoforms with similar affinity and disrupt protein-protein interactions at JNK's D-recruitment site, making them a good candidate for specific non-ATP competitive inhibitors. However, (-)-zuonin A inhibits 80% of JNK catalyzed reactions at saturating levels, while (+)-zuonin A only inhibits 15%. Molecular docking and molecular dynamics simulations were performed to gain a better understanding of how these inhibitors interact JNK. The results of this study provide an alternative binding mode for (-)-zuonin A, compared to one proposed in a previous study, that shows (-)-zuonin A interacting with JNK via an induced fit mechanism by forming a larger pocket for itself near the highly conserved [phi]A-X-[phi]B recognition site, a dynamic move not seen in (+)-zuonin A simulations, and may help explain their different inhibition patterns. / text
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/25261 |
| Date | 22 July 2014 |
| Creators | Dykstra, Daniel William |
| Source Sets | University of Texas |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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