2hu6
From Proteopedia
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| - | [[Image:2hu6.jpg|left|200px]] | + | [[Image:2hu6.jpg|left|200px]] |
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| - | '''Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor''' | + | {{Structure |
| + | |PDB= 2hu6 |SIZE=350|CAPTION= <scene name='initialview01'>2hu6</scene>, resolution 1.32Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=37A:(1S,5S,7R)-N~7~-(BIPHENYL-4-YLMETHYL)-N~3~-HYDROXY-6,8-DIOXA-3-AZABICYCLO[3.2.1]OCTANE-3,7-DICARBOXAMIDE'>37A</scene> and <scene name='pdbligand=HAE:ACETOHYDROXAMIC ACID'>HAE</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] | ||
| + | |GENE= MMP12, HME ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2HU6 is a [ | + | 2HU6 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HU6 OCA]. |
==Reference== | ==Reference== | ||
| - | Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors., Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A, Bioorg Med Chem. 2006 Nov 15;14(22):7392-403. Epub 2006 Aug 8. PMID:[http:// | + | Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors., Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A, Bioorg Med Chem. 2006 Nov 15;14(22):7392-403. Epub 2006 Aug 8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16899369 16899369] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Macrophage elastase]] | [[Category: Macrophage elastase]] | ||
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[[Category: mmp-12]] | [[Category: mmp-12]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:21:37 2008'' |
Revision as of 15:21, 20 March 2008
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| , resolution 1.32Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , and | ||||||
| Gene: | MMP12, HME (Homo sapiens) | ||||||
| Activity: | Macrophage elastase, with EC number 3.4.24.65 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor
Contents |
Overview
Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).
Disease
Known diseases associated with this structure: Cardiomyopathy, dilated, 1G OMIM:[188840], Cardiomyopathy, familial hypertrophic OMIM:[188840], Muscular dystrophy, limb-girdle, type 2J OMIM:[188840], Myopathy, early-onset, with fatal cardiomyopathy OMIM:[188840], Myopathy, proximal, with early respiratory muscle involvement OMIM:[188840], Tibial muscular dystrophy, tardive OMIM:[188840]
About this Structure
2HU6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors., Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A, Bioorg Med Chem. 2006 Nov 15;14(22):7392-403. Epub 2006 Aug 8. PMID:16899369
Page seeded by OCA on Thu Mar 20 17:21:37 2008
