1a85: Difference between revisions
New page: left|200px<br /> <applet load="1a85" size="450" color="white" frame="true" align="right" spinBox="true" caption="1a85, resolution 2.0Å" /> '''MMP8 WITH MALONIC AN... |
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[[Image:1a85.gif|left|200px]]<br /> | [[Image:1a85.gif|left|200px]]<br /><applet load="1a85" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1a85, resolution 2.0Å" /> | caption="1a85, resolution 2.0Å" /> | ||
'''MMP8 WITH MALONIC AND ASPARAGINE BASED INHIBITOR'''<br /> | '''MMP8 WITH MALONIC AND ASPARAGINE BASED INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes | Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures. | ||
==About this Structure== | ==About this Structure== | ||
1A85 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 CA, ZN and HMI as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Neutrophil_collagenase Neutrophil collagenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.34 3.4.24.34] Full crystallographic information is available from [http:// | 1A85 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=CA:'>CA</scene>, <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=HMI:'>HMI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Neutrophil_collagenase Neutrophil collagenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.34 3.4.24.34] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A85 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Brandstetter, H.]] | [[Category: Brandstetter, H.]] | ||
[[Category: Engh, R | [[Category: Engh, R A.]] | ||
[[Category: Grams, F.]] | [[Category: Grams, F.]] | ||
[[Category: Roedern, E | [[Category: Roedern, E G.V.]] | ||
[[Category: CA]] | [[Category: CA]] | ||
[[Category: HMI]] | [[Category: HMI]] | ||
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[[Category: mmp8]] | [[Category: mmp8]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:41:59 2008'' | ||
Revision as of 12:42, 21 February 2008
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MMP8 WITH MALONIC AND ASPARAGINE BASED INHIBITOR
OverviewOverview
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.
About this StructureAbout this Structure
1A85 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Neutrophil collagenase, with EC number 3.4.24.34 Full crystallographic information is available from OCA.
ReferenceReference
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data., Brandstetter H, Engh RA, Von Roedern EG, Moroder L, Huber R, Bode W, Grams F, Protein Sci. 1998 Jun;7(6):1303-9. PMID:9655333
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