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1tl9
From Proteopedia
(New page: 200px<br /><applet load="1tl9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tl9, resolution 1.80Å" /> '''High resolution crys...) |
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| - | [[Image:1tl9.jpg|left|200px]]<br /><applet load="1tl9" size=" | + | [[Image:1tl9.jpg|left|200px]]<br /><applet load="1tl9" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1tl9, resolution 1.80Å" /> | caption="1tl9, resolution 1.80Å" /> | ||
'''High resolution crystal structure of calpain I protease core in complex with leupeptin'''<br /> | '''High resolution crystal structure of calpain I protease core in complex with leupeptin'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The endogenous calpain inhibitor, calpastatin, modulates some | + | The endogenous calpain inhibitor, calpastatin, modulates some patho-physiological aspects of calpain signaling. Excess calpain can escape this inhibition and as well, many calpain isoforms and autolytically generated protease core fragments are not inhibited by calpastatin. There is a need, therefore, to develop specific, cell-permeable calpain inhibitors to block uncontrolled proteolysis and prevent tissue damage during brain and heart ischemia, spinal-cord injury and Alzheimer's diseases. Here, we report the first high-resolution crystal structures of rat mu-calpain protease core complexed with two traditional, low molecular mass inhibitors, leupeptin and E64. These structures show that access to a slightly deeper, but otherwise papain-like active site is gated by two flexible loops. These loops are divergent among the calpain isoforms giving a potential structural basis for substrate/inhibitor selectivity over other papain-like cysteine proteases and between members of the calpain family. |
==About this Structure== | ==About this Structure== | ||
| - | 1TL9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with CA and ACE as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Calpain-1 Calpain-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.52 3.4.22.52] Full crystallographic information is available from [http:// | + | 1TL9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=ACE:'>ACE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Calpain-1 Calpain-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.52 3.4.22.52] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TL9 OCA]. |
==Reference== | ==Reference== | ||
| Line 14: | Line 14: | ||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Campbell, R | + | [[Category: Campbell, R L.]] |
[[Category: Cuerrier, D.]] | [[Category: Cuerrier, D.]] | ||
| - | [[Category: Davies, P | + | [[Category: Davies, P L.]] |
[[Category: Moldoveanu, T.]] | [[Category: Moldoveanu, T.]] | ||
[[Category: ACE]] | [[Category: ACE]] | ||
| Line 22: | Line 22: | ||
[[Category: covalently-linked inhibitor at the active site cysteine forms a hemithioacetal]] | [[Category: covalently-linked inhibitor at the active site cysteine forms a hemithioacetal]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:14:50 2008'' |
Revision as of 13:14, 21 February 2008
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High resolution crystal structure of calpain I protease core in complex with leupeptin
Overview
The endogenous calpain inhibitor, calpastatin, modulates some patho-physiological aspects of calpain signaling. Excess calpain can escape this inhibition and as well, many calpain isoforms and autolytically generated protease core fragments are not inhibited by calpastatin. There is a need, therefore, to develop specific, cell-permeable calpain inhibitors to block uncontrolled proteolysis and prevent tissue damage during brain and heart ischemia, spinal-cord injury and Alzheimer's diseases. Here, we report the first high-resolution crystal structures of rat mu-calpain protease core complexed with two traditional, low molecular mass inhibitors, leupeptin and E64. These structures show that access to a slightly deeper, but otherwise papain-like active site is gated by two flexible loops. These loops are divergent among the calpain isoforms giving a potential structural basis for substrate/inhibitor selectivity over other papain-like cysteine proteases and between members of the calpain family.
About this Structure
1TL9 is a Single protein structure of sequence from Rattus norvegicus with and as ligands. Active as Calpain-1, with EC number 3.4.22.52 Full crystallographic information is available from OCA.
Reference
Crystal structures of calpain-E64 and -leupeptin inhibitor complexes reveal mobile loops gating the active site., Moldoveanu T, Campbell RL, Cuerrier D, Davies PL, J Mol Biol. 2004 Nov 5;343(5):1313-26. PMID:15491615
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