1f9e: Difference between revisions

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[[Image:1f9e.gif|left|200px]]<br />

[[Image:1f9e.gif|left|200px]]<br /><applet load="1f9e" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="1f9e" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1f9e, resolution 2.9Å" />

'''CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO'''<br />

==Overview==

Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the, downstream executioner caspase-3 is a physiological target. Caspases are, cysteine proteases that are specific for substrates with an aspartic acid, residue at the P(1) position and have an optimal recognition motif that, incorporates four amino acid residues N-terminal to the cleavage site., Caspase-8 has been classified as a group III caspase member because it, shows a preference for a small hydrophobic residue at the P(4) substrate, position. We report the X-ray crystallographic structure of caspase-8 in, complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a, specific group II caspase inhibitor. The structure shows that the, inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic, data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor, of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1, nM). In view of this finding, the original classification of caspases into, three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue, Asp in subsite S(4). We propose that the subsite S(3) must be considered, as an important specificity-determining factor.

Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P(1) position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P(4) substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S(4). We propose that the subsite S(3) must be considered as an important specificity-determining factor.

==Disease==

Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]]

Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Lung cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]]

==About this Structure==

1F9E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=1F9E OCA].

1F9E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=1F9E OCA].

==Reference==

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Line 18:

[[Category: Blanchard, H.]]

[[Category: Donepudi, M.]]

[[Category: Grutter, M.G.]]

[[Category: Grutter, M G.]]

[[Category: Kodandapani, L.]]

[[Category: Tschopp, M.]]

[[Category: Wu, J.C.]]

[[Category: Wu, J C.]]

[[Category: apoptosis]]

[[Category: caspase-8]]

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[[Category: mch5]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov~~ 12 16:50:~~18 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:36:16 2008''

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-[[Image:1f9e.gif|left|200px]]<br />
+[[Image:1f9e.gif|left|200px]]<br /><applet load="1f9e" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1f9e" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1f9e, resolution 2.9&Aring;" />
 '''CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO'''<br />
 ==Overview==
-Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the, downstream executioner caspase-3 is a physiological target. Caspases are, cysteine proteases that are specific for substrates with an aspartic acid, residue at the P(1) position and have an optimal recognition motif that, incorporates four amino acid residues N-terminal to the cleavage site., Caspase-8 has been classified as a group III caspase member because it, shows a preference for a small hydrophobic residue at the P(4) substrate, position. We report the X-ray crystallographic structure of caspase-8 in, complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a, specific group II caspase inhibitor. The structure shows that the, inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic, data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor, of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1, nM). In view of this finding, the original classification of caspases into, three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue, Asp in subsite S(4). We propose that the subsite S(3) must be considered, as an important specificity-determining factor.
+Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P(1) position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P(4) substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S(4). We propose that the subsite S(3) must be considered as an important specificity-determining factor.
 ==Disease==
-Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]]
+Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Lung cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]]
 ==About this Structure==
-F9E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=1F9E OCA].
+F9E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=1F9E OCA].
 ==Reference==
@@ Line 19: / Line 18: @@
 [[Category: Blanchard, H.]]
 [[Category: Donepudi, M.]]
-[[Category: Grutter, M.G.]]
+[[Category: Grutter, M G.]]
 [[Category: Kodandapani, L.]]
 [[Category: Tschopp, M.]]
-[[Category: Wu, J.C.]]
+[[Category: Wu, J C.]]
 [[Category: apoptosis]]
 [[Category: caspase-8]]
@@ Line 31: / Line 30: @@
 [[Category: mch5]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:50:18 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:36:16 2008''