Sandbox Reserved 954: Difference between revisions
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When a cystein protease attacks a substrate, the peptide bond cleavage is catalyzed. Firstly, the catalytic cysteine performs a nucleophilic attack on the substrate peptide bond. Thus the new N-terminusis is released and a new bond between the enzyme and the substrate is created forming a covalent enzyme-substrate complex called the acyl enzyme intermediate. Finally, this new bond is hydrolysed and the new C-terminus is released. | When a cystein protease attacks a substrate, the peptide bond cleavage is catalyzed. Firstly, the catalytic cysteine performs a nucleophilic attack on the substrate peptide bond. Thus the new N-terminusis is released and a new bond between the enzyme and the substrate is created forming a covalent enzyme-substrate complex called the acyl enzyme intermediate. Finally, this new bond is hydrolysed and the new C-terminus is released. | ||
===Protease inhibition=== | ===Protease inhibition=== | ||
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The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is cleaved at a scissile bond between two residues <scene name='60/604473/P1_scene/3'>Ser354 termed P1 (N-terminal of the cleavage event) and Ser355 termed P1’ (C-terminal of the cleavage event)</scene>. The <scene name='60/604473/P1_scene/3'>P1 and P1' residues</scene> are the necessary condition for target protease specificity. Indeed, the mutation of these residues results destroys inhibitory activity. The protease recognize <scene name='60/604473/Amino_acids_for_protease_recog/1'>amino-acids of the RCL</scene> that allow its docking. | The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is cleaved at a scissile bond between two residues <scene name='60/604473/P1_scene/3'>Ser354 termed P1 (N-terminal of the cleavage event) and Ser355 termed P1’ (C-terminal of the cleavage event)</scene>. The <scene name='60/604473/P1_scene/3'>P1 and P1' residues</scene> are the necessary condition for target protease specificity. Indeed, the mutation of these residues results destroys inhibitory activity. The protease recognize <scene name='60/604473/Amino_acids_for_protease_recog/1'>amino-acids of the RCL</scene> that allow its docking. | ||
<ref>M. S. J. Mangan, D. Kaiserman & P. I. Bird, The role of serpins in vertebrate immunity | <ref>M. S. J. Mangan, D. Kaiserman & P. I. Bird, The role of serpins in vertebrate immunity | ||
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australiahttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-0039.2008.01059.x/pdf DOI : 10.1111/j.1399-0039.2008.01059.x/pdf </ref> http://genome.cshlp.org/content/10/12/1845 | Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australiahttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-0039.2008.01059.x/pdf DOI : 10.1111/j.1399-0039.2008.01059.x/pdf </ref> <ref>James A. Irving1, Robert N. Pike1, Arthur M. Lesk2, and James C. Whisstock1, Phylogeny of the Serpin Superfamily: Implications of Patterns of Amino Acid Conservation for Structure and Function, http://genome.cshlp.org/content/10/12/1845 DOI : content/10/12/1845</ref> | ||
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Before the hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes from Stressed to Relaxed transition. The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> remains covalently attached to the protease, however the protease is moved from the top to the bottom of SCCA1. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0104935 | Before the hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes from Stressed to Relaxed transition. The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> remains covalently attached to the protease, however the protease is moved from the top to the bottom of SCCA1. <ref> Sílvia Gomes, Patrícia I. Marques,Rune Matthiesen, Susana Seixas, Adaptive Evolution and Divergence of SERPINB3: A Young Duplicate in Great Apes,http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0104935 DOI : 10.1371%2Fjournal.pone.0104935<ref> | ||
This move induce a protease distortion into a conformation, in which the acyl enzyme intermediate is hydrolysed extremely slowly. The active site of the enzyme would be expected to break.The protease thus remains covalently attached to the target protease and is thereby inhibited. | This move induce a protease distortion into a conformation, in which the acyl enzyme intermediate is hydrolysed extremely slowly. The active site of the enzyme would be expected to break.The protease thus remains covalently attached to the target protease and is thereby inhibited. | ||
