==Test Molecule for CBI workshop 11/19/14==
<StructureSection load='3EDR' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Derek MacPherson/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

2013-12-03T15:31:16Z

Derek MacPherson:

Maureen E. Hill/Sandbox1

2013-12-03T15:29:54Z

Derek MacPherson:

== Caspase-7 Dynamics ==
<StructureSection load='1f1j' size='350' side='right' caption='Structure of caspase-7(PDB entry [[1f1j]])' scene=''>

== Background ==

Caspases are cysteine-aspartate proteases that are responsible for the execution of apoptosis, also known as programmed cell death. Dysregulation of apoptosis has been linked to neurodegenerative disorders, including Alzheimer's and Huntington's, as well as inflammatory diseases and cancer.

The apoptotic caspases consist of two distinct classes: the initiators (caspase -2, -8, -9, and -10) and the executioners (caspase -3, -6, and -7). All caspases are synthesized as catalytically inactive zymogens that must undergo proteolytic cleavage to be activated during apoptosis. Initiator caspases are activated by upstream cellular events, which in turn cleave at distinct internal aspartate residues in the executioner caspases to remove the prodomain and separate the large and small subunits. The executioner caspases then cleave a wide range of targets within the cell that ultimately leads to cellular suicide.

== Caspase-7 Structure ==
[[Image:CASP7cleavagesites.jpg | thumb| Cleavage sites of caspase-7]]
Caspases are crystallized as homodimers. As previously stated, the caspases undergo proteolytic cleavage by the initiator caspases to assume their active conformations. Some caspases undergo more cleave than others. For executioner caspase-7 there exists three major cleavage sites, D23, D198 and D207. D23 processing removes the pro domain from the large subunit, where as, D198 and D207 is the major cleavage site for processing and removal of the inter-subunit linker. Caspase-7 has one minor cleavage site also located within the inter-subunit linker at D192.

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/2'>Caspase-7 bound to suicide inhibitor/substrate mimic DEVD-CHO</scene> traps the protein an active/substrate bound conformation. Substrate binding forces L2' to move upward, creating a foundation beneath the L2 bundle.

== Allosteric Inhibition of Caspase-7 ==
It has been shown that caspases -3 and -7 can be inhibited at a site other than the active site by allosteric inhibitors, such as 5-Fluoro-1H-indole-2-carboxylic acid (2-mercapto-ethyl)-amide ('''FICA''') or 2-(2,4-Dichlorophenoxy)-N-(2-mercapto-ethyl)-acetamide ('''DICA'''), at the dimer-interface cavity. The mechanism of these inhibitors lock the L2' in a down conformation, thereby inactivating the enzyme.

<scene name='56/566502/Dica_bound_caspase_7/2'>Caspase-7 bound to allosteric inhibitor DICA</scene> at the dimer interface. The allosteric inhibitor binds to C290 within the dimer interface displacing Y223. The displacement of tyrosine from the active site conformation of the enzyme forces R187 into a position that both physically blocks substrate binding, as well as, move the active site cystine 186. Ultimately, these conformational changes inactivate the enzyme.

== Forms of Caspase-7 ==

<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.

== References ==

File:CASP7cleavagesites.jpg

2013-12-03T15:24:37Z

Derek MacPherson: uploaded a new version of "Image:CASP7cleavagesites.jpg"

2013-12-02T23:12:15Z

Derek MacPherson: uploaded a new version of "Image:CASP7cleavagesites.jpg"

Maureen E. Hill/Sandbox1

2013-12-02T23:10:46Z

Derek MacPherson:

== Caspase-7 Dynamics ==
<StructureSection load='1f1j' size='350' side='right' caption='Structure of caspase-7(PDB entry [[1f1j]])' scene=''>

== Background ==

Caspases are cysteine-aspartate proteases that are responsible for the execution of apoptosis, also known as programmed cell death. Dysregulation of apoptosis has been linked to neurodegenerative disorders, including Alzheimer's and Huntington's, as well as inflammatory diseases and cancer.

The apoptotic caspases consist of two distinct classes: the initiators (caspase -2, -8, -9, and -10) and the executioners (caspase -3, -6, and -7). All caspases are synthesized as catalytically inactive zymogens that must undergo proteolytic cleavage to be activated during apoptosis. Initiator caspases are activated by upstream cellular events, which in turn cleave at distinct internal aspartate residues in the executioner caspases to remove the prodomain and separate the large and small subunits. The executioner caspases then cleave a wide range of targets within the cell that ultimately leads to cellular suicide.

== Caspase-7 Structure ==

[[Image:CASP7cleavagesites.jpg]]
Caspases are crystallized as homodimers. Each monomer contains a large (~20 kDa) and a small (~10 kDa) subunit. 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/2'>Caspase-7 bound to suicide inhibitor/substrate mimic DEVD-CHO</scene> traps the protein an active/substrate bound conformation. Substrate binding forces L2' to move upward, creating a foundation beneath the L2 bundle. However, it has been shown that if caspase-7 were to bind an allosteric inhibitor, such as 5-Fluoro-1H-indole-2-carboxylic acid (2-mercapto-ethyl)-amide ('''FICA''') or 2-(2,4-Dichlorophenoxy)-N-(2-mercapto-ethyl)-acetamide ('''DICA'''), at the dimer-interface cavity, the L2' loop would be locked in the down conformation, thereby inactivating the enzyme.

== Forms of Caspase-7 ==

*<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='56/566502/Dica_bound_caspase_7/2'>Caspase-7 bound to allosteric inhibitor DICA</scene> at the dimer interface. The allosteric inhibitor binds to C290 within the dimer interface displacing Y223. The displacement of tyrosine from the active site conformation of the enzyme forces R187 into a position that both physically blocks substrate binding, as well as, move the active site cystine 186. Ultimately, these conformational changes inactivate the enzyme.

*<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.

2013-12-02T20:51:44Z

Derek MacPherson:

== Caspase-7 Dynamics ==
<StructureSection load='1f1j' size='350' side='right' caption='Structure of caspase-7(PDB entry [[1f1j]])' scene=''>

== Background ==

Caspases are cysteine-aspartate proteases that are responsible for the execution of apoptosis, also known as programmed cell death. Dysregulation of apoptosis has been linked to neurodegenerative disorders, including Alzheimer's and Huntington's, as well as inflammatory diseases and cancer.

The apoptotic caspases consist of two distinct classes: the initiators (caspase -2, -8, -9, and -10) and the executioners (caspase -3, -6, and -7). All caspases are synthesized as catalytically inactive zymogens that must undergo proteolytic cleavage to be activated during apoptosis. Initiator caspases are activated by upstream cellular events, which in turn cleave at distinct internal aspartate residues in the executioner caspases to remove the prodomain and separate the large and small subunits. The executioner caspases then cleave a wide range of targets within the cell that ultimately leads to cellular suicide.

== Caspase-7 Structure ==

Caspases are crystallized as homodimers. Each monomer contains a large (~20 kDa) and a small (~10 kDa) subunit. 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-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, it has been shown that if caspase-7 were to bind an allosteric inhibitor, such as 5-Fluoro-1H-indole-2-carboxylic acid (2-mercapto-ethyl)-amide ('''FICA''') or 2-(2,4-Dichlorophenoxy)-N-(2-mercapto-ethyl)-acetamide ('''DICA'''), at the dimer-interface cavity, the L2' loop would be locked in the down conformation, thereby inactivating the enzyme.

<scene name='56/566502/Zoom_bundle/1'>Loop bundle</scene>

== Forms of Caspase-7 ==

*<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.