1b8y: Difference between revisions
No edit summary |
No edit summary |
||
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
Effective inhibitors of matrix metalloproteinases (MMPs), a family of | Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 A. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S'1 pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S'1 pocket. The largest differences occur in the loop forming the "top" of this pocket. The occupation of these nonpeptidic inhibitors in the S'1 pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors. | ||
==Disease== | ==Disease== | ||
| Line 17: | Line 17: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Stromelysin 1]] | [[Category: Stromelysin 1]] | ||
[[Category: Blundell, T | [[Category: Blundell, T L.]] | ||
[[Category: Dhanaraj, V.]] | [[Category: Dhanaraj, V.]] | ||
[[Category: Humblet, C.]] | [[Category: Humblet, C.]] | ||
[[Category: Hupe, D.]] | [[Category: Hupe, D.]] | ||
[[Category: II, C | [[Category: II, C F.Purchase.]] | ||
[[Category: Johnson, L | [[Category: Johnson, L L.]] | ||
[[Category: Ortwine, D | [[Category: Ortwine, D F.]] | ||
[[Category: Pavlovsky, A | [[Category: Pavlovsky, A G.]] | ||
[[Category: Roth, B | [[Category: Roth, B D.]] | ||
[[Category: White, A | [[Category: White, A D.]] | ||
[[Category: Williams, M | [[Category: Williams, M G.]] | ||
[[Category: Ye, Q | [[Category: Ye, Q Z.]] | ||
[[Category: CA]] | [[Category: CA]] | ||
[[Category: IN7]] | [[Category: IN7]] | ||
| Line 37: | Line 37: | ||
[[Category: stromelysin-1]] | [[Category: stromelysin-1]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:52:47 2008'' | ||
Revision as of 12:52, 21 February 2008
|
X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXED WITH NON-PEPTIDE INHIBITORS: IMPLICATIONS FOR INHIBITOR SELECTIVITY
OverviewOverview
Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 A. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S'1 pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S'1 pocket. The largest differences occur in the loop forming the "top" of this pocket. The occupation of these nonpeptidic inhibitors in the S'1 pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.
DiseaseDisease
Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[185250]
About this StructureAbout this Structure
1B8Y 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 Full crystallographic information is available from OCA.
ReferenceReference
X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity., Pavlovsky AG, Williams MG, Ye QZ, Ortwine DF, Purchase CF 2nd, White AD, Dhanaraj V, Roth BD, Johnson LL, Hupe D, Humblet C, Blundell TL, Protein Sci. 1999 Jul;8(7):1455-62. PMID:10422833
Page seeded by OCA on Thu Feb 21 11:52:47 2008