Elucidating binding modes of zuonin A enantiomers to JNK1 via in silico methods

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.

Name thesis:degree_name

Master of Arts

Level thesis:degree_level

Masters

Discipline thesis:degree_discipline

Biochemistry

Grantor

The University of Texas at Austin

Year dc:date.issued

2013

Author dc:creator

• Dykstra, Daniel William

Advisor dc:contributor.advisor

• Ren, Pengyu

• JNK
• Zuonin A
• Molecular dynamics
• Molecular docking
• MM-GBSA

Handle dc:identifier.uri

http://hdl.handle.net/2152/25261

OAI identifier oai:identifier

oai:repositories.lib.utexas.edu:2152/25261