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Clark Lab

Department of Biology
University of Texas at Arlington

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Using Zebrafish in cancer drug design









Conformational Changes in Procaspase-3

The intersubunit linker binds in the dimer interface and stabilizes the inactive conformer. The active conformer of the procaspase forms when the linker is removed from the interface, either by cleavage of the polypeptide chain or by mutagenesis.





Conformational Changes in Procaspase-3

In this movie, caspase-3 is shown in a space-filling model whereas the intersubunit linker is shown as the yellow ribbon. The models show the movement of the intersubunit linker in caspase-3 as the protein conformation changes from inactive to active. The red region is the dimer interface.






Activation of Procaspase-3

Procaspase-3 is activated after cleavage of the intersubunit linker (IL). In the procaspase, the IL binds in the dimer interface and prevents the active site loops from organizing. After cleavage the IL from one monomer interacts with the active site of the second monomer. Active Site Loops: Yellow=loop 1; Red=loop 2; Blue=loop 3; Brown=loop 4; Cyan=loop 2'.






Active Site Loop Formation

Upon cleavage of the intersubunit linker, R164 from active site loop 2 (L2) moves from a solvent exposed position into the dimer interface, where it intercalates between Y197 and P201. Red=loop 2; Blue=loop 3; Brown=loop 4.






Allosteric Inhibition of Caspase-3 by V266 to His Mutation

A mutation of V266 to His in the dimer interface inactivates the enzyme. The His side chain causes steric clashes that ultimately result in population of the inactive ensemble of native states.







Molecular Dynamics Simulation of Caspase-3

A 50 ns simulation of caspase-3 without inhibitor bound. The simulation (green) is overlaid with the crystal structure of unliganded caspase-3 (blue).







Allostery, Apoptosis, Caspases, Cancer Biology, Protein Engineering, X-ray Crystallography, Spectroscopy (Equilibrium and Kinetic Studies), Isother mal Titration Calorimetry, Analytical Ultracentrifugation, Molecular Modeling, Molecular Dynamics, Site-Directed Mutagenesis, Assay Development, Transfection, Western Analysis, RT-PCR, Cell Sorting, Transgenic Animals, Phage Display

About Me

Clay Clark is Professor and Chair of Biology at the University of Texas at Arlington. He joined the faculty in 2015. More / Contact ...

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