2gpl
From Proteopedia
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| - | [[Image:2gpl.gif|left|200px]] | + | [[Image:2gpl.gif|left|200px]] |
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| - | '''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors''' | + | {{Structure |
| + | |PDB= 2gpl |SIZE=350|CAPTION= <scene name='initialview01'>2gpl</scene>, resolution 2.81Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=BIQ:BENZYL [12-(2-AMINO-2-OXOETHYL)-4-NITRO-10,13-DIOXO-15-[(PROPYLAMINO)CARBONYL]-2-OXA-11,14-DIAZATRICYCLO[15 .2.2.1~3,7~]DOCOSA-1(19),3(22),4,6,17,20-HEXAEN-9-YL]CARBAMATE'>BIQ</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.25.1 3.4.25.1] | ||
| + | |GENE= PRS4, PRE8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRE1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRE2, DOA3, PRG1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRS3, PRE7, PTS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRE4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRE3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRS5, PRE9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRE6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PUP2, DOA5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRE5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRS1, PRC1, PRE10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PRS2, PRC2, SCL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PUP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]), PUP3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae]) | ||
| + | }} | ||
| + | |||
| + | '''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2GPL is a [ | + | 2GPL is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GPL OCA]. |
==Reference== | ==Reference== | ||
| - | TMC-95-based inhibitor design provides evidence for the catalytic versatility of the proteasome., Groll M, Gotz M, Kaiser M, Weyher E, Moroder L, Chem Biol. 2006 Jun;13(6):607-14. PMID:[http:// | + | TMC-95-based inhibitor design provides evidence for the catalytic versatility of the proteasome., Groll M, Gotz M, Kaiser M, Weyher E, Moroder L, Chem Biol. 2006 Jun;13(6):607-14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16793518 16793518] |
[[Category: Proteasome endopeptidase complex]] | [[Category: Proteasome endopeptidase complex]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices; ntn-hydrolase]] | [[Category: proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices; ntn-hydrolase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:07:27 2008'' |
Revision as of 15:07, 20 March 2008
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| , resolution 2.81Å | |||||||
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| Ligands: | |||||||
| Gene: | PRS4, PRE8 (Saccharomyces cerevisiae), PRE1 (Saccharomyces cerevisiae), PRE2, DOA3, PRG1 (Saccharomyces cerevisiae), PRS3, PRE7, PTS1 (Saccharomyces cerevisiae), PRE4 (Saccharomyces cerevisiae), PRE3 (Saccharomyces cerevisiae), PRS5, PRE9 (Saccharomyces cerevisiae), PRE6 (Saccharomyces cerevisiae), PUP2, DOA5 (Saccharomyces cerevisiae), PRE5 (Saccharomyces cerevisiae), PRS1, PRC1, PRE10 (Saccharomyces cerevisiae), PRS2, PRC2, SCL1 (Saccharomyces cerevisiae), PUP1 (Saccharomyces cerevisiae), PUP3 (Saccharomyces cerevisiae) | ||||||
| Activity: | Proteasome endopeptidase complex, with EC number 3.4.25.1 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors
Overview
TMC-95's natural cyclic tripeptide metabolites represent potent competitive proteasome inhibitors. The constrained conformation of TMC-95 proteasomal inhibitors provides the driving force for entropically high-affinity binding. Based on the crystal structure of the proteasome:TMC-95A complex, the synthetically challenging TMC-95 core structure was used for the design and synthesis of less demanding biphenyl-ether macrocycles, in which the biphenyl-ether moiety functions as an endocyclic clamp restricting its tripeptide backbone. These simplified analogs allowed us to identify high plasticity of the proteasomal tryptic-like specificity pocket. Biphenyl-ether compounds extended with an amide group were hydrolyzed by the proteasome, although the crystal structure of such proteasome:biphenyl-ether complexes revealed quenching of proteolysis at the acyl-enzyme intermediate. Our data reveal that biphenyl-ether derivatives bind noncovalently to the proteasomal tryptic-like active site in a reversible substrate-like manner without allosteric changes of active site residues.
About this Structure
2GPL is a Protein complex structure of sequences from Saccharomyces cerevisiae. Full crystallographic information is available from OCA.
Reference
TMC-95-based inhibitor design provides evidence for the catalytic versatility of the proteasome., Groll M, Gotz M, Kaiser M, Weyher E, Moroder L, Chem Biol. 2006 Jun;13(6):607-14. PMID:16793518
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