Maureen E. Hill/Sandbox1
From Proteopedia
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=== Caspase-7 Dynamics === | === Caspase-7 Dynamics === | ||
<StructureSection load='1f1j' size='350' side='right' caption='Structure of caspase-7(PDB entry [[1f1j]])' scene=''> | <StructureSection load='1f1j' size='350' side='right' caption='Structure of caspase-7(PDB entry [[1f1j]])' scene=''> | ||
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+ | Caspases are a family of [[CBI Molecules]] being studied in the <span class="plainlinks">[http://www.umass.edu/cbi/ University of Massachusetts Amherst Chemistry-Biology Interface Program]</span> at UMass Amherst and on display at the <span class="plainlinks">[http://www.molecularplayground.org/ Molecular Playground]</span>. | ||
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+ | === Caspase-7 as studied in <span class="plainlinks">[http://www.chem.umass.edu/~jhardy/ the Hardy Lab] </span>=== | ||
+ | <applet load='Caspmorph.pdb' size='300' frame='true' scene='Molecular_Playground/Caspase_Dynamics/Morph2/2' align='right' caption='Conformational Dynamics between active and allosterically inhibited caspase-7 elucidate the mechanism of allostery in this important class of cysteine proteases.' /> | ||
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+ | Conformational dynamics in Caspase-7 are mediated by an 'Allosteric Toggle' mechanism in which binding of allosteric inhibitor DICA to CYS 290 pushes TYR 223 into 'up' conformation forcing ARG 187 'out' into a form that is physically incompatible with substrate binding. | ||
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+ | The cleaved termini of the large and small subunits which form the active site loop bundle become highly ordered in active conformation, and highly disordered in allosterically inhibited form (so much so that they cannot be resolved crystallographically). | ||
=== Background === | === Background === | ||
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Caspases are crystallized as homodimers. Each monomer contains a large (~20 kDa) and a small (~10 kDa) subunit. The active site 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-7_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. Substrate binding forces L2' to move upward, creating a foundation beneath the L2 bundle. However, if caspase-7 were to bind an allosteric inhibitor at the dimer-interface cavity, the L2' loop would be locked in the down conformation, thereby inactivating the enzyme. | Caspases are crystallized as homodimers. Each monomer contains a large (~20 kDa) and a small (~10 kDa) subunit. The active site 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-7_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. Substrate binding forces L2' to move upward, creating a foundation beneath the L2 bundle. However, if caspase-7 were to bind an allosteric inhibitor at the dimer-interface cavity, the L2' loop would be locked in the down conformation, thereby inactivating the enzyme. | ||
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+ | === Forms of Caspase-7 === | ||
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+ | *<scene name='Molecular_Playground/Caspase_Dynamics/1f1j/2'>Caspase-7 bound to suicide inhibitor/substrate mimic DEVD-CHO</scene>, trapping protein in active/substrate bound conformation. | ||
+ | *<scene name='Molecular_Playground/Caspase_Dynamics/1shj-234234/1'>Caspase-7 bound to allosteric inhibitor DICA through CYS290</scene> trapping protein in a form incompatible with substrate binding. | ||
+ | *<scene name='Molecular_Playground/Caspase_Dynamics/Morph2/2'>Conformational change between substrate bound and substrate incompatible forms</scene> of Caspase-7. | ||
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+ | === Molecular Playground banner for Caspase-7 === | ||
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+ | '''Molecular Playground banner:''' Conformational Dynamics between active and allosterically inhibited caspase-7 elucidate the mechanism of allostery in this important class of cysteine proteases. | ||
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+ | ==3D structures of caspase== | ||
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+ | [[Caspase]] | ||
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+ | ==Additional Resources== | ||
+ | For additional information, see: [[Cancer]] | ||
+ | <br /> | ||
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<scene name='56/566502/Zoom_bundle/1'>Loop bundle</scene> | <scene name='56/566502/Zoom_bundle/1'>Loop bundle</scene> |
Revision as of 18:48, 2 December 2013
Caspase-7 Dynamics
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