1utz: Difference between revisions
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|PDB= 1utz |SIZE=350|CAPTION= <scene name='initialview01'>1utz</scene>, resolution 2.5Å | |PDB= 1utz |SIZE=350|CAPTION= <scene name='initialview01'>1utz</scene>, resolution 2.5Å | ||
|SITE= <scene name='pdbsite=ZN2:Ca+Binding+Site+For+Chain+B'>ZN2</scene> | |SITE= <scene name='pdbsite=ZN2:Ca+Binding+Site+For+Chain+B'>ZN2</scene> | ||
|LIGAND= <scene name='pdbligand= | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=PF3:(2R)-3-({[4-[(PYRIDIN-4-YL)PHENYL]-THIEN-2-YL}CARBOXAMIDO)(PHENYL)PROPANOIC+ACID'>PF3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/Macrophage_elastase Macrophage elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.65 3.4.24.65] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Macrophage_elastase Macrophage elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.65 3.4.24.65] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1utz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1utz OCA], [http://www.ebi.ac.uk/pdbsum/1utz PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1utz RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed. | Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Perrier, S.]] | [[Category: Perrier, S.]] | ||
[[Category: Tertre, A.]] | [[Category: Tertre, A.]] | ||
[[Category: hydrolase]] | [[Category: hydrolase]] | ||
[[Category: macrophage metalloelastase]] | [[Category: macrophage metalloelastase]] | ||
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[[Category: non-zinc chelator]] | [[Category: non-zinc chelator]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:15:18 2008'' | ||
Revision as of 00:15, 31 March 2008
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| , resolution 2.5Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , , | ||||||
| Activity: | Macrophage elastase, with EC number 3.4.24.65 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF MMP-12 COMPLEXED TO (2R)-3-({[4-[(PYRI DIN-4-YL)PHENYL]-THIEN-2-YL}CARBOXAMIDO)(PHENYL)PROPANOIC ACID
OverviewOverview
Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed.
About this StructureAbout this Structure
1UTZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12., Morales R, Perrier S, Florent JM, Beltra J, Dufour S, De Mendez I, Manceau P, Tertre A, Moreau F, Compere D, Dublanchet AC, O'Gara M, J Mol Biol. 2004 Aug 20;341(4):1063-76. PMID:15289103
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