View source for 4l19


==Matrix metalloproteinase-13 complexed with selective inhibitor compound Q1==
<StructureSection load='4l19' size='340' side='right'caption='[[4l19]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4l19]] 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=4L19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L19 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.66&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1UA:2-[(4-METHYLBENZYL)SULFANYL]-3,5,6,7-TETRAHYDRO-4H-CYCLOPENTA[D]PYRIMIDIN-4-ONE'>1UA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4l19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l19 OCA], [https://pdbe.org/4l19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l19 RCSB], [https://www.ebi.ac.uk/pdbsum/4l19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l19 ProSAT]</span></td></tr>
</table>
== 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure-activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug-drug interactions in humans.

Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro.,Spicer TP, Jiang J, Taylor AB, Choi JY, Hart PJ, Roush WR, Fields GB, Hodder PS, Minond D J Med Chem. 2014 Nov 26;57(22):9598-611. doi: 10.1021/jm501284e. Epub 2014 Nov, 11. PMID:25330343<ref>PMID:25330343</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4l19" style="background-color:#fffaf0;"></div>

==See Also==
*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fields GB]]
[[Category: Hart PJ]]
[[Category: Hodder PS]]
[[Category: Jiang J]]
[[Category: Minond D]]
[[Category: Roush WR]]
[[Category: Spicer TP]]
[[Category: Taylor AB]]