1d7x: Difference between revisions
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|PDB= 1d7x |SIZE=350|CAPTION= <scene name='initialview01'>1d7x</scene>, resolution 2.Å | |PDB= 1d7x |SIZE=350|CAPTION= <scene name='initialview01'>1d7x</scene>, resolution 2.Å | ||
|SITE= | |SITE= | ||
|LIGAND= | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SPC:N-HYDROXY+1N(4-METHOXYPHENYL)SULFONYL-4-(Z,E-N-METHOXYIMINO)PYRROLIDINE-2R-CARBOXAMIDE'>SPC</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=[[1cqr|1CQR]], [[1d5j|1D5J]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1d7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d7x OCA], [http://www.ebi.ac.uk/pdbsum/1d7x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1d7x RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated. | The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Natchus, M G.]] | [[Category: Natchus, M G.]] | ||
[[Category: Pikul, S.]] | [[Category: Pikul, S.]] | ||
[[Category: inhibited]] | [[Category: inhibited]] | ||
[[Category: mixed alpha beta structure]] | [[Category: mixed alpha beta structure]] | ||
[[Category: zinc protease]] | [[Category: zinc protease]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:36:23 2008'' | ||
Revision as of 19:36, 30 March 2008
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| , resolution 2.Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Activity: | Stromelysin 1, with EC number 3.4.24.17 | ||||||
| Related: | 1CQR, 1D5J
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A MODIFIED PROLINE SCAFFOLD BASED INHIBITOR.
OverviewOverview
The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.
About this StructureAbout this Structure
1D7X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold., Cheng M, De B, Almstead NG, Pikul S, Dowty ME, Dietsch CR, Dunaway CM, Gu F, Hsieh LC, Janusz MJ, Taiwo YO, Natchus MG, Hudlicky T, Mandel M, J Med Chem. 1999 Dec 30;42(26):5426-36. PMID:10639284
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