1you

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[[Image:1you.gif|left|200px]]
[[Image:1you.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1you |SIZE=350|CAPTION= <scene name='initialview01'>1you</scene>, resolution 2.30&Aring;
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The line below this paragraph, containing "STRUCTURE_1you", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PFD:5-(2-ETHOXYETHYL)-5-[4-(4-FLUOROPHENOXY)PHENOXY]PYRIMIDINE-2,4,6(1H,3H,5H)-TRIONE'>PFD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY=
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or leave the SCENE parameter empty for the default display.
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|GENE= MMP13 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_1you| PDB=1you | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1you FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1you OCA], [http://www.ebi.ac.uk/pdbsum/1you PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1you RCSB]</span>
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}}
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'''Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor'''
'''Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor'''
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[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Pandit, J.]]
[[Category: Pandit, J.]]
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[[Category: hydrolase]]
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[[Category: Hydrolase]]
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[[Category: metalloprotease]]
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[[Category: Metalloprotease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 16:35:35 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:15:54 2008''
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Revision as of 13:35, 3 May 2008

Image:1you.gif

Template:STRUCTURE 1you

Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor


Overview

Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.

About this Structure

1YOU is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14., Blagg JA, Noe MC, Wolf-Gouveia LA, Reiter LA, Laird ER, Chang SP, Danley DE, Downs JT, Elliott NC, Eskra JD, Griffiths RJ, Hardink JR, Haugeto AI, Jones CS, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robinson RP, Subramanyam C, Vaughn-Bowser ML, Yocum SA, Bioorg Med Chem Lett. 2005 Apr 1;15(7):1807-10. PMID:15780611 Page seeded by OCA on Sat May 3 16:35:35 2008

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OCA

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