1hfs: Difference between revisions
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==About this Structure== | ==About this Structure== | ||
1HFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, CA and L04 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <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>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HFS OCA]. | 1HFS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:ZINC ION'>ZN</scene>, <scene name='pdbligand=CA:CALCIUM ION'>CA</scene> and <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> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <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>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HFS OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: proteoglycanase]] | [[Category: proteoglycanase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Dec 19 13:19:35 2007'' | ||
Revision as of 14:09, 19 December 2007
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CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THE N-CARBOXY-ALKYL INHIBITOR L-764,004
OverviewOverview
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).
DiseaseDisease
Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[185250]
About this StructureAbout this Structure
1HFS is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Stromelysin 1, with EC number 3.4.24.17 Known structural/functional Sites: , , , , and . Full crystallographic information is available from OCA.
ReferenceReference
Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides., Esser CK, Bugianesi RL, Caldwell CG, Chapman KT, Durette PL, Girotra NN, Kopka IE, Lanza TJ, Levorse DA, MacCoss M, Owens KA, Ponpipom MM, Simeone JP, Harrison RK, Niedzwiecki L, Becker JW, Marcy AI, Axel MG, Christen AJ, McDonnell J, Moore VL, Olszewski JM, Saphos C, Visco DM, Hagmann WK, et al., J Med Chem. 1997 Mar 14;40(6):1026-40. PMID:9083493
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