1qx3

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(New page: 200px<br /> <applet load="1qx3" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qx3, resolution 1.90&Aring;" /> '''Conformational rest...)
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'''Conformational restrictions in the active site of unliganded human caspase-3'''<br />
'''Conformational restrictions in the active site of unliganded human caspase-3'''<br />
==Overview==
==Overview==
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Caspases are cysteine proteases that play a critical role in the, initiation and regulation of apoptosis. These enzymes act in a cascade to, promote cell death through proteolytic cleavage of intracellular proteins., Since activation of apoptosis is implicated in human diseases such as, cancer and neurodegenerative disorders, caspases are targets for drugs, designed to modulate their action. Active caspases are heterodimeric, enzymes with two symmetrically arranged active sites at opposite ends of, the molecule. A number of crystal structures of caspases with peptides or, proteins bound at the active sites have defined the mechanism of action of, these enzymes, but molecular information about the active sites before, substrate engagement has been lacking. As part of a study of peptidyl, inhibitors of caspase-3, we crystallized a complex where the inhibitor did, not bind in the active site. Here we present the crystal structure of the, unoccupied substrate-binding site of caspase-3. No large conformational, differences were apparent when this site was compared with that in, enzyme-inhibitor complexes. Instead, the 1.9 A structure reveals critical, side chain movements in a hydrophobic pocket in the active site. Notably, the side chain of tyrosine204 is rotated by approximately 90 degrees so, that the phenol group occupies the S2 subsite in the active site. Thus, binding of substrate or inhibitors is impeded unless rotation of this side, chain opens the area. The positions of these side chains may have, important implications for the directed design of inhibitors of caspase-3, or caspase-7.
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Caspases are cysteine proteases that play a critical role in the initiation and regulation of apoptosis. These enzymes act in a cascade to promote cell death through proteolytic cleavage of intracellular proteins. Since activation of apoptosis is implicated in human diseases such as cancer and neurodegenerative disorders, caspases are targets for drugs designed to modulate their action. Active caspases are heterodimeric enzymes with two symmetrically arranged active sites at opposite ends of the molecule. A number of crystal structures of caspases with peptides or proteins bound at the active sites have defined the mechanism of action of these enzymes, but molecular information about the active sites before substrate engagement has been lacking. As part of a study of peptidyl inhibitors of caspase-3, we crystallized a complex where the inhibitor did not bind in the active site. Here we present the crystal structure of the unoccupied substrate-binding site of caspase-3. No large conformational differences were apparent when this site was compared with that in enzyme-inhibitor complexes. Instead, the 1.9 A structure reveals critical side chain movements in a hydrophobic pocket in the active site. Notably, the side chain of tyrosine204 is rotated by approximately 90 degrees so that the phenol group occupies the S2 subsite in the active site. Thus, binding of substrate or inhibitors is impeded unless rotation of this side chain opens the area. The positions of these side chains may have important implications for the directed design of inhibitors of caspase-3 or caspase-7.
==About this Structure==
==About this Structure==
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1QX3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QX3 OCA].
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1QX3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QX3 OCA].
==Reference==
==Reference==
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: Ely, K.R.]]
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[[Category: Ely, K R.]]
[[Category: Li, C.]]
[[Category: Li, C.]]
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[[Category: Ni, C.Z.]]
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[[Category: Ni, C Z.]]
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[[Category: Spada, A.P.]]
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[[Category: Spada, A P.]]
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[[Category: Wu, J.C.]]
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[[Category: Wu, J C.]]
[[Category: active site]]
[[Category: active site]]
[[Category: apoptosis]]
[[Category: apoptosis]]
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[[Category: cysteine protease]]
[[Category: cysteine protease]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:57:14 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:44:45 2008''

Revision as of 12:44, 21 February 2008


1qx3, resolution 1.90Å

Drag the structure with the mouse to rotate

Conformational restrictions in the active site of unliganded human caspase-3

Overview

Caspases are cysteine proteases that play a critical role in the initiation and regulation of apoptosis. These enzymes act in a cascade to promote cell death through proteolytic cleavage of intracellular proteins. Since activation of apoptosis is implicated in human diseases such as cancer and neurodegenerative disorders, caspases are targets for drugs designed to modulate their action. Active caspases are heterodimeric enzymes with two symmetrically arranged active sites at opposite ends of the molecule. A number of crystal structures of caspases with peptides or proteins bound at the active sites have defined the mechanism of action of these enzymes, but molecular information about the active sites before substrate engagement has been lacking. As part of a study of peptidyl inhibitors of caspase-3, we crystallized a complex where the inhibitor did not bind in the active site. Here we present the crystal structure of the unoccupied substrate-binding site of caspase-3. No large conformational differences were apparent when this site was compared with that in enzyme-inhibitor complexes. Instead, the 1.9 A structure reveals critical side chain movements in a hydrophobic pocket in the active site. Notably, the side chain of tyrosine204 is rotated by approximately 90 degrees so that the phenol group occupies the S2 subsite in the active site. Thus, binding of substrate or inhibitors is impeded unless rotation of this side chain opens the area. The positions of these side chains may have important implications for the directed design of inhibitors of caspase-3 or caspase-7.

About this Structure

1QX3 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Conformational restrictions in the active site of unliganded human caspase-3., Ni CZ, Li C, Wu JC, Spada AP, Ely KR, J Mol Recognit. 2003 May-Jun;16(3):121-4. PMID:12833566

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