1cte: Difference between revisions

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CRYSTAL STRUCTURES OF RECOMBINANT RAT CATHEPSIN B AND A CATHEPSIN B-INHIBITOR COMPLEX: IMPLICATIONS FOR STRUCTURE-BASED INHIBITOR DESIGN

OverviewOverview

The lysosomal cysteine proteinase cathepsin B (EC 3.4.22.1) plays an important role in protein catabolism and has also been implicated in various disease states. The crystal structures of two forms of native recombinant rat cathepsin B have been determined. The overall folding of rat cathepsin B was shown to be very similar to that of the human liver enzyme. The structure of the native enzyme containing an underivatized active site cysteine (Cys29) showed the active enzyme conformation to be similar to that determined previously for the oxidized form. In a second structure Cys29 was derivatized with the reversible blocking reagent pyridyl disulfide. In this structure large side chain conformational changes were observed for the two key catalytic residues Cys29 and His199, demonstrating the potential flexibility of these side chains. In addition the structure of the complex between rat cathepsin B and the inhibitor benzyloxycarbonyl-Arg-Ser(O-Bzl) chloromethylketone was determined. The complex structure showed that very little conformational change occurs in the enzyme upon inhibitor binding. It also allowed visualization of the interaction between the enzyme and inhibitor. In particular the interaction between Glu245 and the P2 Arg residue was clearly demonstrated, and it was found that the benzyl group of the P1 substrate residue occupies a large hydrophobic pocket thought to represent the S'1 subsite. This may have important implications for structure-based design of cathepsin B inhibitors.

About this StructureAbout this Structure

1CTE is a Single protein structure of sequence from Rattus norvegicus with as ligand. Active as Cathepsin B, with EC number 3.4.22.1 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of recombinant rat cathepsin B and a cathepsin B-inhibitor complex. Implications for structure-based inhibitor design., Jia Z, Hasnain S, Hirama T, Lee X, Mort JS, To R, Huber CP, J Biol Chem. 1995 Mar 10;270(10):5527-33. PMID:7890671

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-[[Image:1cte.gif|left|200px]]<br /><applet load="1cte" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1cte.gif|left|200px]]<br /><applet load="1cte" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1cte, resolution 2.1&Aring;" />
 '''CRYSTAL STRUCTURES OF RECOMBINANT RAT CATHEPSIN B AND A CATHEPSIN B-INHIBITOR COMPLEX: IMPLICATIONS FOR STRUCTURE-BASED INHIBITOR DESIGN'''<br />
 ==Overview==
-The lysosomal cysteine proteinase cathepsin B (EC 3.4.22.1) plays an, important role in protein catabolism and has also been implicated in, various disease states. The crystal structures of two forms of native, recombinant rat cathepsin B have been determined. The overall folding of, rat cathepsin B was shown to be very similar to that of the human liver, enzyme. The structure of the native enzyme containing an underivatized, active site cysteine (Cys29) showed the active enzyme conformation to be, similar to that determined previously for the oxidized form. In a second, structure Cys29 was derivatized with the reversible blocking reagent, pyridyl disulfide. In this structure large side chain conformational, changes were observed for the two key catalytic residues Cys29 and His199, demonstrating the potential flexibility of these side chains. In addition, the structure of the complex between rat cathepsin B and the inhibitor, benzyloxycarbonyl-Arg-Ser(O-Bzl) chloromethylketone was determined. The, complex structure showed that very little conformational change occurs in, the enzyme upon inhibitor binding. It also allowed visualization of the, interaction between the enzyme and inhibitor. In particular the, interaction between Glu245 and the P2 Arg residue was clearly, demonstrated, and it was found that the benzyl group of the P1 substrate, residue occupies a large hydrophobic pocket thought to represent the S'1, subsite. This may have important implications for structure-based design, of cathepsin B inhibitors.
+The lysosomal cysteine proteinase cathepsin B (EC 3.4.22.1) plays an important role in protein catabolism and has also been implicated in various disease states. The crystal structures of two forms of native recombinant rat cathepsin B have been determined. The overall folding of rat cathepsin B was shown to be very similar to that of the human liver enzyme. The structure of the native enzyme containing an underivatized active site cysteine (Cys29) showed the active enzyme conformation to be similar to that determined previously for the oxidized form. In a second structure Cys29 was derivatized with the reversible blocking reagent pyridyl disulfide. In this structure large side chain conformational changes were observed for the two key catalytic residues Cys29 and His199, demonstrating the potential flexibility of these side chains. In addition the structure of the complex between rat cathepsin B and the inhibitor benzyloxycarbonyl-Arg-Ser(O-Bzl) chloromethylketone was determined. The complex structure showed that very little conformational change occurs in the enzyme upon inhibitor binding. It also allowed visualization of the interaction between the enzyme and inhibitor. In particular the interaction between Glu245 and the P2 Arg residue was clearly demonstrated, and it was found that the benzyl group of the P1 substrate residue occupies a large hydrophobic pocket thought to represent the S'1 subsite. This may have important implications for structure-based design of cathepsin B inhibitors.
 ==About this Structure==
-CTE 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 PYS as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Cathepsin_B Cathepsin B], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.1 3.4.22.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1CTE OCA].
+CTE 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=PYS:'>PYS</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Cathepsin_B Cathepsin B], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.1 3.4.22.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CTE OCA].
 ==Reference==
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 [[Category: Rattus norvegicus]]
 [[Category: Single protein]]
-[[Category: Huber, C.P.]]
+[[Category: Huber, C P.]]
 [[Category: Jia, Z.]]
 [[Category: PYS]]
 [[Category: thiol protease]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 12:44:44 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:09:30 2008''