Proteopedia

2ozr: Difference between revisions

← Older edit
No edit summary
No edit summary
 
(14 intermediate revisions by the same user not shown)
Line 1: Line 1:
[[Image:2ozr.gif|left|200px]]


{{Structure
==MMP13 Catalytic Domain Complexed with 4-{[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydroquinazolin-3(2H)-yl]methyl}benzoic acid==
|PDB= 2ozr |SIZE=350|CAPTION= <scene name='initialview01'>2ozr</scene>, resolution 2.300&Aring;
<StructureSection load='2ozr' size='340' side='right'caption='[[2ozr]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GG1:4-{[1-METHYL-2,4-DIOXO-6-(3-PHENYLPROP-1-YN-1-YL)-1,4-DIHYDROQUINAZOLIN-3(2H)-YL]METHYL}BENZOIC+ACID'>GG1</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
<table><tr><td colspan='2'>[[2ozr]] is a 8 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=2OZR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OZR FirstGlance]. <br>
|ACTIVITY=  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
|GENE= MMP13 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GG1:4-{[1-METHYL-2,4-DIOXO-6-(3-PHENYLPROP-1-YN-1-YL)-1,4-DIHYDROQUINAZOLIN-3(2H)-YL]METHYL}BENZOIC+ACID'>GG1</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ozr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ozr OCA], [https://pdbe.org/2ozr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ozr RCSB], [https://www.ebi.ac.uk/pdbsum/2ozr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ozr ProSAT]</span></td></tr>
|RELATEDENTRY=[[2ow9|2OW9]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ozr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ozr OCA], [http://www.ebi.ac.uk/pdbsum/2ozr PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ozr RCSB]</span>
== Disease ==
}}
[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 ==
[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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/oz/2ozr_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=2ozr ConSurf].
<div style="clear:both"></div>


'''MMP13 Catalytic Domain Complexed with 4-{[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydroquinazolin-3(2H)-yl]methyl}benzoic acid'''
==See Also==
 
*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
 
== References ==
==Overview==
<references/>
Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.
__TOC__
 
</StructureSection>
==About this Structure==
2OZR 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=2OZR OCA].
 
==Reference==
Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects., Johnson AR, Pavlovsky AG, Ortwine DF, Prior F, Man CF, Bornemeier DA, Banotai CA, Mueller WT, McConnell P, Yan C, Baragi V, Lesch C, Roark WH, Wilson M, Datta K, Guzman R, Han HK, Dyer RD, J Biol Chem. 2007 Sep 21;282(38):27781-91. Epub 2007 Jul 10. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17623656 17623656]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Banotai, C A.]]
[[Category: Banotai CA]]
[[Category: Baragi, V.]]
[[Category: Baragi V]]
[[Category: Bornemeier, D A.]]
[[Category: Bornemeier DA]]
[[Category: Datta, K.]]
[[Category: Datta K]]
[[Category: Dyer, R D.]]
[[Category: Dyer RD]]
[[Category: Fasquelle, V.]]
[[Category: Fasquelle V]]
[[Category: Guzman, R.]]
[[Category: Guzman R]]
[[Category: Han, H K.]]
[[Category: Han H-K]]
[[Category: Johnson, A R.]]
[[Category: Johnson AR]]
[[Category: Lesch, C.]]
[[Category: Lesch C]]
[[Category: Lie, J J.]]
[[Category: Lie JJ]]
[[Category: Man, C F.]]
[[Category: Man C-F]]
[[Category: McConnell, P.]]
[[Category: McConnell P]]
[[Category: Mueller, W T.]]
[[Category: Mueller WT]]
[[Category: Ortwine, D F.]]
[[Category: Ortwine DF]]
[[Category: Pavlovsky, A G.]]
[[Category: Pavlovsky AG]]
[[Category: Prior, F.]]
[[Category: Prior F]]
[[Category: Roark, W H.]]
[[Category: Roark WH]]
[[Category: Robertson, D.]]
[[Category: Robertson D]]
[[Category: Wilson, M.]]
[[Category: Wilson M]]
[[Category: Yan, C H.]]
[[Category: Yan CH]]
[[Category: crystal complex structure]]
[[Category: hydrolase]]
[[Category: matrix metalloproteinase]]
[[Category: mmp13 catalytic domain]]
[[Category: mmp13 specific inhibitor]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:25:38 2008''

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/w/2ozr"