3elm

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==Crystal Structure of MMP-13 Complexed with Inhibitor 24f==
==Crystal Structure of MMP-13 Complexed with Inhibitor 24f==
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<StructureSection load='3elm' size='340' side='right' caption='[[3elm]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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<StructureSection load='3elm' size='340' side='right'caption='[[3elm]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3elm]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ELM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ELM FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3elm]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ELM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ELM FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=24F:(2R)-({[5-(4-ETHOXYPHENYL)THIOPHEN-2-YL]SULFONYL}AMINO){1-[(1-METHYLETHOXY)CARBONYL]PIPERIDIN-4-YL}ETHANOIC+ACID'>24F</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MMP13 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=24F:(2R)-({[5-(4-ETHOXYPHENYL)THIOPHEN-2-YL]SULFONYL}AMINO){1-[(1-METHYLETHOXY)CARBONYL]PIPERIDIN-4-YL}ETHANOIC+ACID'>24F</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3elm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3elm OCA], [http://pdbe.org/3elm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3elm RCSB], [http://www.ebi.ac.uk/pdbsum/3elm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3elm ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3elm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3elm OCA], [https://pdbe.org/3elm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3elm RCSB], [https://www.ebi.ac.uk/pdbsum/3elm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3elm ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/MMP13_HUMAN MMP13_HUMAN]] Defects in MMP13 are the cause of spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM:[http://omim.org/entry/602111 602111]]. A bone disease characterized by moderate to severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood. Epimetaphyseal changes improve with age.<ref>PMID:16167086</ref> Defects in MMP13 are the cause of metaphyseal anadysplasia type 1 (MANDP1) [MIM:[http://omim.org/entry/602111 602111]]. Metaphyseal anadysplasia consists of an abnormal bone development characterized by severe skeletal changes that, in contrast with the progressive course of most other skeletal dysplasias, resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia.<ref>PMID:19615667</ref>
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[https://www.uniprot.org/uniprot/MMP13_HUMAN MMP13_HUMAN] Defects in MMP13 are the cause of spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM:[https://omim.org/entry/602111 602111]. A bone disease characterized by moderate to severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood. Epimetaphyseal changes improve with age.<ref>PMID:16167086</ref> Defects in MMP13 are the cause of metaphyseal anadysplasia type 1 (MANDP1) [MIM:[https://omim.org/entry/602111 602111]. Metaphyseal anadysplasia consists of an abnormal bone development characterized by severe skeletal changes that, in contrast with the progressive course of most other skeletal dysplasias, resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia.<ref>PMID:19615667</ref>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MMP13_HUMAN MMP13_HUMAN]] Degrades collagen type I. Does not act on gelatin or casein. Could have a role in tumoral process.
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[https://www.uniprot.org/uniprot/MMP13_HUMAN MMP13_HUMAN] Degrades collagen type I. Does not act on gelatin or casein. Could have a role in tumoral process.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
<jmolCheckbox>
<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/el/3elm_consurf.spt"</scriptWhenChecked>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/el/3elm_consurf.spt"</scriptWhenChecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
<text>to colour the structure by Evolutionary Conservation</text>
<text>to colour the structure by Evolutionary Conservation</text>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3elm ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3elm ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
 
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== Publication Abstract from PubMed ==
 
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The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of &gt;10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p &lt; 0.05) and at 10 mg/kg (40% inhibition, p &lt; 0.05).
 
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Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13.,Monovich LG, Tommasi RA, Fujimoto RA, Blancuzzi V, Clark K, Cornell WD, Doti R, Doughty J, Fang J, Farley D, Fitt J, Ganu V, Goldberg R, Goldstein R, Lavoie S, Kulathila R, Macchia W, Parker DT, Melton R, O'Byrne E, Pastor G, Pellas T, Quadros E, Reel N, Roland DM, Sakane Y, Singh H, Skiles J, Somers J, Toscano K, Wigg A, Zhou S, Zhu L, Shieh WC, Xue S, McQuire LW J Med Chem. 2009 Jun 11;52(11):3523-38. PMID:19422229<ref>PMID:19422229</ref>
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==See Also==
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*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3elm" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Koehn, J]]
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[[Category: Large Structures]]
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[[Category: Kulathila, R]]
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[[Category: Koehn J]]
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[[Category: Monovich, L]]
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[[Category: Kulathila R]]
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[[Category: Calcium]]
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[[Category: Monovich L]]
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[[Category: Carboxylate inhibitor]]
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[[Category: Collagen degradation]]
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[[Category: Disease mutation]]
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[[Category: Extracellular matrix]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Metal-binding]]
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[[Category: Metallo-enzyme]]
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[[Category: Metalloprotease]]
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[[Category: Mmp-13]]
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[[Category: Polymorphism]]
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[[Category: Protease]]
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[[Category: Secreted]]
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[[Category: Zinc]]
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[[Category: Zymogen]]
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Current revision

Crystal Structure of MMP-13 Complexed with Inhibitor 24f

PDB ID 3elm

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