3zxh

From Proteopedia

(Difference between revisions)

Revision as of 07:08, 5 August 2016

MMP-13 COMPLEXED WITH 2-NAPTHYLSULFONAMIDE HYDROXAMIC ACID INHIBITOR

Structural highlights

3zxh 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:	1fls, 2yig, 1eub, 1xur, 1you, 1fm1, 456c, 1uc1, 830c, 1xuc, 1pex, 1ztq, 2d1n, 1xud
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

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 provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which exhibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.

Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13.,Tommasi RA, Weiler S, McQuire LW, Rogel O, Chambers M, Clark K, Doughty J, Fang J, Ganu V, Grob J, Goldberg R, Goldstein R, Lavoie S, Kulathila R, Macchia W, Melton R, Springer C, Walker M, Zhang J, Zhu L, Shultz M Bioorg Med Chem Lett. 2011 Nov 1;21(21):6440-5. Epub 2011 Aug 27. PMID:21937229^[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
↑ Tommasi RA, Weiler S, McQuire LW, Rogel O, Chambers M, Clark K, Doughty J, Fang J, Ganu V, Grob J, Goldberg R, Goldstein R, Lavoie S, Kulathila R, Macchia W, Melton R, Springer C, Walker M, Zhang J, Zhu L, Shultz M. Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6440-5. Epub 2011 Aug 27. PMID:21937229 doi:10.1016/j.bmcl.2011.08.087

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/3zxh"

@@ Line 1: / Line 1: @@
 ==MMP-13 COMPLEXED WITH 2-NAPTHYLSULFONAMIDE HYDROXAMIC ACID INHIBITOR==
 <StructureSection load='3zxh' size='340' side='right' caption='[[3zxh]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3zxh]] is a 2 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=3ZXH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZXH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3zxh]] 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=3ZXH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZXH 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=E41:N-HYDROXY-N^2^-(3-METHYLBUTYL)-N^2^-(NAPHTHALEN-2-YLSULFONYL)-D-VALINAMIDE'>E41</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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">[[1fls|1fls]], [[2yig|2yig]], [[1eub|1eub]], [[1xur|1xur]], [[1you|1you]], [[1fm1|1fm1]], [[456c|456c]], [[1uc1|1uc1]], [[830c|830c]], [[1xuc|1xuc]], [[1pex|1pex]], [[1ztq|1ztq]], [[2d1n|2d1n]], [[1xud|1xud]]</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=3zxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zxh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zxh RCSB], [http://www.ebi.ac.uk/pdbsum/3zxh 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=3zxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zxh OCA], [http://pdbe.org/3zxh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zxh RCSB], [http://www.ebi.ac.uk/pdbsum/3zxh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zxh ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3zxh" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Clark, K L]]
 [[Category: Kulathila, R]]

3zxh

From Proteopedia

Revision as of 07:08, 5 August 2016

MMP-13 COMPLEXED WITH 2-NAPTHYLSULFONAMIDE HYDROXAMIC ACID INHIBITOR

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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