1hfs: Difference between revisions
No edit summary |
No edit summary |
||
| Line 4: | Line 4: | ||
|PDB= 1hfs |SIZE=350|CAPTION= <scene name='initialview01'>1hfs</scene>, resolution 1.70Å | |PDB= 1hfs |SIZE=350|CAPTION= <scene name='initialview01'>1hfs</scene>, resolution 1.70Å | ||
|SITE= <scene name='pdbsite=CA1:Ligands+Of+Ca+Ion+Ca+259'>CA1</scene>, <scene name='pdbsite=CA2:Ligands+Of+Ca+Ion+Ca+260'>CA2</scene>, <scene name='pdbsite=CA3:Ligands+Of+Ca+Ion+Ca+261'>CA3</scene>, <scene name='pdbsite=L04:Binding+Site+For+The+Inhibitor+L-764,004,+Denoted+L04+256'>L04</scene>, <scene name='pdbsite=ZN1:Ligands+Of+Catalytic+(Zn+257)+Zn+Ion'>ZN1</scene> and <scene name='pdbsite=ZN2:Ligands+Of+Structural+(Zn+258)+Zn+Ion'>ZN2</scene> | |SITE= <scene name='pdbsite=CA1:Ligands+Of+Ca+Ion+Ca+259'>CA1</scene>, <scene name='pdbsite=CA2:Ligands+Of+Ca+Ion+Ca+260'>CA2</scene>, <scene name='pdbsite=CA3:Ligands+Of+Ca+Ion+Ca+261'>CA3</scene>, <scene name='pdbsite=L04:Binding+Site+For+The+Inhibitor+L-764,004,+Denoted+L04+256'>L04</scene>, <scene name='pdbsite=ZN1:Ligands+Of+Catalytic+(Zn+257)+Zn+Ion'>ZN1</scene> and <scene name='pdbsite=ZN2:Ligands+Of+Structural+(Zn+258)+Zn+Ion'>ZN2</scene> | ||
|LIGAND= | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=L04:6-(4'-FLUORO-BIPHENYL-4-YL)-4-(3-METHYL-1-PHENYLCARBAMOYL-BUTYLCARBAMOYL)-2-[4-(1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-BUTYL]-HEXANOIC+ACID'>L04</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hfs OCA], [http://www.ebi.ac.uk/pdbsum/1hfs PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1hfs RCSB]</span> | |||
}} | }} | ||
| Line 14: | Line 17: | ||
==Overview== | ==Overview== | ||
Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv). | Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv). | ||
==About this Structure== | ==About this Structure== | ||
| Line 27: | Line 27: | ||
[[Category: Stromelysin 1]] | [[Category: Stromelysin 1]] | ||
[[Category: Becker, J W.]] | [[Category: Becker, J W.]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
[[Category: matrix metalloprotease-3]] | [[Category: matrix metalloprotease-3]] | ||
| Line 35: | Line 32: | ||
[[Category: proteoglycanase]] | [[Category: proteoglycanase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:04:14 2008'' | ||