3tvc: Difference between revisions
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==Human MMP13 in complex with L-glutamate motif inhibitor== | |||
=== | <StructureSection load='3tvc' size='340' side='right' caption='[[3tvc]], [[Resolution|resolution]] 2.43Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3tvc]] is a 1 chain structure with 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=3TVC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TVC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=E3P:N~2~-[3-(1,1 4,1-TERPHENYL-4-YL)PROPANOYL]-L-ALPHA-GLUTAMINE'>E3P</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qj2|3qj2]], [[1xuc|1xuc]], [[3kec|3kec]], [[3ts4|3ts4]], [[3tsk|3tsk]], [[3tt4|3tt4]]</td></tr> | |||
<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 Homo sapiens])</td></tr> | |||
<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=3tvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tvc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tvc RCSB], [http://www.ebi.ac.uk/pdbsum/3tvc PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[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> | |||
== Function == | |||
[[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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A series of pseudo-peptides with general formula X-l-Glu-NH(2) (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P(2)' l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins. | |||
Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.,Devel L, Beau F, Amoura M, Vera L, Cassar-Lajeunesse E, Garcia S, Czarny B, Stura EA, Dive V J Biol Chem. 2012 Aug 3;287(32):26647-56. Epub 2012 Jun 11. PMID:22689580<ref>PMID:22689580</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
<references | *[[Matrix metalloproteinase|Matrix metalloproteinase]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Beau, F | [[Category: Beau, F]] | ||
[[Category: Cassar-Lajeunesse, E | [[Category: Cassar-Lajeunesse, E]] | ||
[[Category: Czarny, B | [[Category: Czarny, B]] | ||
[[Category: Devel, L | [[Category: Devel, L]] | ||
[[Category: Dive, V | [[Category: Dive, V]] | ||
[[Category: Stura, E A | [[Category: Stura, E A]] | ||
[[Category: Vera, L | [[Category: Vera, L]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Metzincin]] | [[Category: Metzincin]] | ||
Revision as of 12:34, 15 February 2015
Human MMP13 in complex with L-glutamate motif inhibitorHuman MMP13 in complex with L-glutamate motif inhibitor
Structural highlights
Disease[MMP13_HUMAN] Defects in MMP13 are the cause of spondyloepimetaphyseal dysplasia Missouri type (SEMD-MO) [MIM: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.[1] Defects in MMP13 are the cause of metaphyseal anadysplasia type 1 (MANDP1) [MIM: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.[2] Function[MMP13_HUMAN] Degrades collagen type I. Does not act on gelatin or casein. Could have a role in tumoral process. Publication Abstract from PubMedA series of pseudo-peptides with general formula X-l-Glu-NH(2) (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P(2)' l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins. Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.,Devel L, Beau F, Amoura M, Vera L, Cassar-Lajeunesse E, Garcia S, Czarny B, Stura EA, Dive V J Biol Chem. 2012 Aug 3;287(32):26647-56. Epub 2012 Jun 11. PMID:22689580[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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