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4jpa

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Revision as of 19:26, 11 August 2016

Mmp13 in complex with a piperazine hydantoin ligand

Structural highlights

4jpa is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	4jp4
Gene:	MMP13 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.

Hydantoin based inhibitors of MMP13--discovery of AZD6605.,De Savi C, Waterson D, Pape A, Lamont S, Hadley E, Mills M, Page KM, Bowyer J, Maciewicz RA Bioorg Med Chem Lett. 2013 Aug 15;23(16):4705-12. doi:, 10.1016/j.bmcl.2013.05.089. Epub 2013 Jun 10. PMID:23810497^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kennedy AM, Inada M, Krane SM, Christie PT, Harding B, Lopez-Otin C, Sanchez LM, Pannett AA, Dearlove A, Hartley C, Byrne MH, Reed AA, Nesbit MA, Whyte MP, Thakker RV. MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO). J Clin Invest. 2005 Oct;115(10):2832-42. PMID:16167086 doi:10.1172/JCI22900
↑ Lausch E, Keppler R, Hilbert K, Cormier-Daire V, Nikkel S, Nishimura G, Unger S, Spranger J, Superti-Furga A, Zabel B. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am J Hum Genet. 2009 Aug;85(2):168-78. doi: 10.1016/j.ajhg.2009.06.014. Epub 2009, Jul 16. PMID:19615667 doi:10.1016/j.ajhg.2009.06.014
↑ De Savi C, Waterson D, Pape A, Lamont S, Hadley E, Mills M, Page KM, Bowyer J, Maciewicz RA. Hydantoin based inhibitors of MMP13--discovery of AZD6605. Bioorg Med Chem Lett. 2013 Aug 15;23(16):4705-12. doi:, 10.1016/j.bmcl.2013.05.089. Epub 2013 Jun 10. PMID:23810497 doi:http://dx.doi.org/10.1016/j.bmcl.2013.05.089

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4jpa"

@@ Line 1: / Line 1: @@
 ==Mmp13 in complex with a piperazine hydantoin ligand==
 <StructureSection load='4jpa' size='340' side='right' caption='[[4jpa]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jp4|4jp4]]</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 HUMAN])</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=4jpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jpa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jpa RCSB], [http://www.ebi.ac.uk/pdbsum/4jpa PDBsum]</span></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=4jpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jpa OCA], [http://pdbe.org/4jpa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jpa RCSB], [http://www.ebi.ac.uk/pdbsum/4jpa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jpa ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4jpa" style="background-color:#fffaf0;"></div>
 ==See Also==

4jpa

From Proteopedia

Revision as of 19:26, 11 August 2016

Mmp13 in complex with a piperazine hydantoin ligand

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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