Molecular Playground/Executioner Caspase-7: Difference between revisions
New page: Caspases are a family of CBI Molecules being studied in the [http://www.chem.umass.edu/~jhardy/ Hardy Lab] in the <span class="plainlinks">[http://www.umass.edu/cbi/ University of Mas... |
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The <scene name='56/566502/Active_site_conformation/1'>active site</scene> is made up of four flexible loops which include L2, L3 and L4 from one half of the dimer that interact with L2' from the opposite half of the dimer. In the <scene name='56/566502/Procaspase_zymogen/1'>procaspase-7 zymogen</scene>, the loops are disordered, which prevents substrate binding. Upon cleavage at the intersubunit linker, the active-site loop bundle becomes partially ordered, whereas L2' stays in the inactive, down conformation. At this point, caspase-7 may bind either substrate or allosteric inhibitors. <scene name='56/566502/Active_site_substrate_color/1'>Caspase-7 bound to suicide inhibitor/substrate mimc DEVD-CHO</scene> traps the protein an active/substrate bound conformation. Substrate binding forces a conformational change moving L2' upward; this creates a foundation beneath the L2 bundle stabilizing the active complex. Mutagenesis performed within this region of the protein has a significant impact on the ability of the protein to process its substrates. Ultimately, this confirms the importance of L2' stabilizing the active site loop bundle. | The <scene name='56/566502/Active_site_conformation/1'>active site</scene> is made up of four flexible loops which include L2, L3 and L4 from one half of the dimer that interact with L2' from the opposite half of the dimer. In the <scene name='56/566502/Procaspase_zymogen/1'>procaspase-7 zymogen</scene>, the loops are disordered, which prevents substrate binding. Upon cleavage at the intersubunit linker, the active-site loop bundle becomes partially ordered, whereas L2' stays in the inactive, down conformation. At this point, caspase-7 may bind either substrate or allosteric inhibitors. <scene name='56/566502/Active_site_substrate_color/1'>Caspase-7 bound to suicide inhibitor/substrate mimc DEVD-CHO</scene> traps the protein an active/substrate bound conformation. Substrate binding forces a conformational change moving L2' upward; this creates a foundation beneath the L2 bundle stabilizing the active complex. Mutagenesis performed within this region of the protein has a significant impact on the ability of the protein to process its substrates. Ultimately, this confirms the importance of L2' stabilizing the active site loop bundle. | ||
== Allosteric Inhibition of Caspase-7 == | == Allosteric Inhibition of Caspase-7 == | ||
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<scene name='56/566502/Dica_bound_caspase_7/2'>Caspase-7 bound to allosteric inhibitor DICA</scene> at the dimer interface. The mechanism of allosteric inhibition of DICA starts with binding to C290 within the dimer interface, this displaces Y223. The movement of tyrosine from the partially active state of the enzyme forces R187 into a position that both physically blocks substrate binding, as well as, move the active site cysteine 186. The resulting conformational changes inactivate the enzyme, making it unable to process substrate. | <scene name='56/566502/Dica_bound_caspase_7/2'>Caspase-7 bound to allosteric inhibitor DICA</scene> at the dimer interface. The mechanism of allosteric inhibition of DICA starts with binding to C290 within the dimer interface, this displaces Y223. The movement of tyrosine from the partially active state of the enzyme forces R187 into a position that both physically blocks substrate binding, as well as, move the active site cysteine 186. The resulting conformational changes inactivate the enzyme, making it unable to process substrate. | ||
== Caspase-7 Dynamics == | == Caspase-7 Dynamics == | ||
Observed here is the <scene name='Molecular_Playground/Caspase_Dynamics/Morph2/2'>conformational change between substrate bound and substrate incompatible forms</scene> of Caspase-7. These dynamics show the dramatic conformational change of the cleaved semi-ordered protease upon binding to the substrate mimic DEVD-CHO. Substrate binding triggers rearrangement of the partially ordered loop bundles and the L2' loop. The newly assumed state stabilizes the protein. | |||
== Notes == | |||
This is an updated version of the [http://www.proteopedia.org/wiki/index.php/Molecular_Playground/Caspase-7_Dynamics Caspase-7 Dynamics] page. | |||
== References == | == References == | ||