@article{maciag_mackenzie_tucker_schipper_swartz_clark_2016, title={Tunable allosteric library of caspase-3 identifies coupling between conserved water molecules and conformational selection}, volume={113}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.1603549113}, abstractNote={Significance}, number={41}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Maciag, Joseph J. and Mackenzie, Sarah H. and Tucker, Matthew B. and Schipper, Joshua L. and Swartz, Paul and Clark, A. Clay}, year={2016}, month={Oct}, pages={E6080–E6088} }
 @article{cade_swartz_mackenzie_clark_2014, title={Modifying Caspase-3 Activity by Altering Allosteric Networks}, volume={53}, ISSN={["0006-2960"]}, DOI={10.1021/bi500874k}, abstractNote={Caspases have several allosteric sites that bind small molecules or peptides. Allosteric regulators are known to affect caspase enzyme activity, in general, by facilitating large conformational changes that convert the active enzyme to a zymogen-like form in which the substrate-binding pocket is disordered. Mutations in presumed allosteric networks also decrease activity, although large structural changes are not observed. Mutation of the central V266 to histidine in the dimer interface of caspase-3 inactivates the enzyme by introducing steric clashes that may ultimately affect positioning of a helix on the protein surface. The helix is thought to connect several residues in the active site to the allosteric dimer interface. In contrast to the effects of small molecule allosteric regulators, the substrate-binding pocket is intact in the mutant, yet the enzyme is inactive. We have examined the putative allosteric network, in particular the role of helix 3, by mutating several residues in the network. We relieved steric clashes in the context of caspase-3(V266H), and we show that activity is restored, particularly when the restorative mutation is close to H266. We also mimicked the V266H mutant by introducing steric clashes elsewhere in the allosteric network, generating several mutants with reduced activity. Overall, the data show that the caspase-3 native ensemble includes the canonical active state as well as an inactive conformation characterized by an intact substrate-binding pocket, but with an altered helix 3. The enzyme activity reflects the relative population of each species in the native ensemble.}, number={48}, journal={BIOCHEMISTRY}, author={Cade, Christine and Swartz, Paul and MacKenzie, Sarah H. and Clark, A. Clay}, year={2014}, month={Dec}, pages={7582–7595} }
 @article{ma_mackenzie_clark_2014, title={Redesigning the procaspase-8 dimer interface for improved dimerization}, volume={23}, number={4}, journal={Protein Science}, author={Ma, C. X. and MacKenzie, S. H. and Clark, A. C.}, year={2014}, pages={442–453} }
 @article{mackenzie_schipper_england_thomas_blackburn_swartz_clark_2013, title={Lengthening the Intersubunit Linker of Procaspase 3 Leads to Constitutive Activation}, volume={52}, ISSN={["0006-2960"]}, DOI={10.1021/bi400793s}, abstractNote={The conformational ensemble of procaspase 3, the primary executioner in apoptosis, contains two major forms, inactive and active, with the inactive state favored in the native ensemble. A region of the protein known as the intersubunit linker (IL) is cleaved during maturation, resulting in movement of the IL out of the dimer interface and subsequent active site formation (activation-by-cleavage mechanism). We examined two models for the role of the IL in maintaining the inactive conformer, an IL-extension model versus a hydrophobic cluster model, and we show that increasing the length of the IL by introducing 3-5 alanines results in constitutively active procaspases. Active site labeling and subsequent analyses by mass spectrometry show that the full-length zymogen is enzymatically active. We also show that minor populations of alternately cleaved procaspase result from processing at D169 when the normal cleavage site, D175, is unavailable. Importantly, the alternately cleaved proteins have little to no activity, but increased flexibility of the linker increases the exposure of D169. The data show that releasing the strain of the short IL, in and of itself, is not sufficient to populate the active conformer of the native ensemble. The IL must also allow for interactions that stabilize the active site, possibly from a combination of optimal length, flexibility in the IL, and specific contacts between the IL and interface. The results provide further evidence that substantial energy is required to shift the protein to the active conformer. As a result, the activation-by-cleavage mechanism dominates in the cell.}, number={36}, journal={BIOCHEMISTRY}, author={MacKenzie, Sarah H. and Schipper, Joshua L. and England, Erika J. and Thomas, Melvin E., III and Blackburn, Kevin and Swartz, Paul and Clark, A. Clay}, year={2013}, month={Sep}, pages={6219–6231} }
 @article{mackenzie_clark_2013, title={Slow folding and assembly of a procaspase-3 interface variant}, volume={52}, number={20}, journal={Biochemistry}, author={MacKenzie, S. H. and Clark, A. C.}, year={2013}, pages={3415–3427} }
 @article{schipper_mackenzie_sharma_clark_2011, title={A bifunctional allosteric site in the dimer interface of procaspase-3}, volume={159}, ISSN={["1873-4200"]}, DOI={10.1016/j.bpc.2011.05.013}, abstractNote={The dimer interface of caspase-3 contains a bifunctional allosteric site in which the enzyme can be activated or inactivated, depending on the context of the protein. In the mature caspase-3, the binding of allosteric inhibitors to the interface results in an order-to-disorder transition in the active site loops. In procaspase-3, by contrast, the binding of allosteric activators to the interface results in a disorder-to-order transition in the active site. We have utilized the allosteric site to identify a small molecule activator of procaspase and to characterize its binding to the protease. The data suggest that an efficient activator must stabilize the active conformer of the zymogen by expelling the intersubunit linker from the interface, and it must interact with active site residues found in the allosteric site. Small molecule activators that fulfill the two requirements should provide scaffolds for drug candidates as a therapeutic strategy for directly promoting procaspase-3 activation in cancer cells.}, number={1}, journal={BIOPHYSICAL CHEMISTRY}, author={Schipper, Joshua L. and MacKenzie, Sarah H. and Sharma, Anil and Clark, A. Clay}, year={2011}, month={Nov}, pages={100–109} }
 @misc{mackenzie_schipper_clark_2010, title={The potential for caspases in drug discovery}, volume={13}, number={5}, journal={Current Opinion in Drug Discovery & Development}, author={MacKenzie, S. H. and Schipper, J. L. and Clark, A. C.}, year={2010}, pages={568–576} }
 @misc{mackenzie_clark_2008, title={Targeting cell death in tumors by activating Caspases}, volume={8}, number={2}, journal={Current Cancer Drug Targets}, author={MacKenzie, S. H. and Clark, A. C.}, year={2008}, pages={98–109} }