| University of Delaware | 327 Wolf Hall | Newark, DE 19716 | <div class="ExternalClassDD3BE557867441C4B7B15C34C9F72998"><p>​<strong>B.S.</strong> - Rensselaer Polytechnic Institute; <strong>Ph.D.</strong> - Perleman School of Medicine, University of Pennsylvania</p></div> | <div class="ExternalClassBB307C63ADE549D3BF48F3AF43244835"><p>​<strong></strong>The mycobacterial Clp proteases are large oligomeric complexes that
comprise a hexameric unfoldase (ClpX or ClpC1) and a heteromeric
barrel-shaped peptidase (ClpP1P2). Biochemical evidence suggests that
protease assembly is dynamic, and that the active form exists in
equilibrium with unassembled inactive species. We aim to characterize
the assembly and disassembly pathways, the kinetics of activation and
inactivation, and the mechanisms by which substrates stimulate activity.</p></div> | <div class="ExternalClass76B76AAC219E4B64A78F8F236B335831"><p>​Clp proteases selectively recognize protein substrates, which minimizes
wasteful and deleterious off-target proteolysis. However, few <em>bona fide</em>
substrates are known in mycobacteria, and the rules that govern
substrate discrimination are not understood. Through targeted screening
and capture-based methods, we aim to identify novel physiological
substrates. We use cell-based and phage-based screening approaches to
define the sequence-based rules by which these proteases select
substrates. We also aim to crystallize protease components in complex
with substrate polypeptides, to determine the specific interactions and
motifs that guide substrate recognition. These studies will help us
understand the role that Clp proteases play in mycobacterial biology,
and will guide the development of novel <em>in vivo</em> reporter substrates.</p></div> | <div class="ExternalClass60EFAC0F1D70416F9598A72C5DBAB08A"><p>​A major motivation for studying Clp protease function is to improve our
ability to develop compounds that disrupt their activity in <em>M. tuberculosis</em>. While we have a rich toolbox of reagents and assays useful for probing protease activity <em>in vitro</em>,
few of these tools are well-suited to high-throughput screening
applications. We are working to develop robust assay platforms with
higher signal-to-noise, improved dynamic range, and the ability to
multiplex reporters for unfolding, peptidase, and protease activities.
We also collaborate with talented synthetic chemists to characterize and
optimize compounds that target these essential mycobacterial enzymes.</p></div> | | | Clp protease assembly and disassembly | Substrate identification and selectivity | High-throughput screening and compound characterization | | | | schmitzk@udel.edu | | Schmitz, Karl | | (302) 831-6100 | <img alt="" src="/Images%20Bios/schmizk.jpg" style="BORDER:0px solid;" /> | Assistant Professor | | | | | | | | | | | | | | | | |
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