1d8f
From Proteopedia
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|PDB= 1d8f |SIZE=350|CAPTION= <scene name='initialview01'>1d8f</scene>, resolution 2.4Å | |PDB= 1d8f |SIZE=350|CAPTION= <scene name='initialview01'>1d8f</scene>, resolution 2.4Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SPI:N-HYDROXY-1-(4-METHOXYPHENYL)SULFONYL-4-BENZYLOXYCARBONYL-PIPERAZINE-2-CARBOXAMIDE'>SPI</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]], [[1d7x|1D7X]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1d8f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d8f OCA], [http://www.ebi.ac.uk/pdbsum/1d8f PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1d8f RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors. | A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=185250 185250]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Snider, C E.]] | [[Category: Snider, C E.]] | ||
[[Category: Taiwo, Y O.]] | [[Category: Taiwo, Y O.]] | ||
| - | [[Category: CA]] | ||
| - | [[Category: SPI]] | ||
| - | [[Category: ZN]] | ||
[[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 19:36:39 2008'' |
Revision as of 16:36, 30 March 2008
| |||||||
| , resolution 2.4Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Activity: | Stromelysin 1, with EC number 3.4.24.17 | ||||||
| Related: | 1CQR, 1D5J, 1D7X
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A PIPERAZINE BASED INHIBITOR.
Overview
A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.
About this Structure
1D8F is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Design and synthesis of piperazine-based matrix metalloproteinase inhibitors., Cheng M, De B, Pikul S, Almstead NG, Natchus MG, Anastasio MV, McPhail SJ, Snider CE, Taiwo YO, Chen L, Dunaway CM, Gu F, Dowty ME, Mieling GE, Janusz MJ, Wang-Weigand S, J Med Chem. 2000 Feb 10;43(3):369-80. PMID:10669564
Page seeded by OCA on Sun Mar 30 19:36:39 2008
