3wv1

From Proteopedia

(Difference between revisions)

Revision as of 17:21, 9 March 2017

Crystal structure of the catalytic domain of MMP-13 complexed with 4-(2-((6-fluoro-2-((3-methoxybenzyl)carbamoyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid

Structural highlights

3wv1 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	3wv2, 3wv3
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

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.,Nara H, Sato K, Naito T, Mototani H, Oki H, Yamamoto Y, Kuno H, Santou T, Kanzaki N, Terauchi J, Uchikawa O, Kori M J Med Chem. 2014 Nov 13;57(21):8886-902. doi: 10.1021/jm500981k. Epub 2014 Oct, 15. PMID:25264600^[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
↑ Nara H, Sato K, Naito T, Mototani H, Oki H, Yamamoto Y, Kuno H, Santou T, Kanzaki N, Terauchi J, Uchikawa O, Kori M. Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach. J Med Chem. 2014 Nov 13;57(21):8886-902. doi: 10.1021/jm500981k. Epub 2014 Oct, 15. PMID:25264600 doi:http://dx.doi.org/10.1021/jm500981k

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3wv1"

Categories: Oki, H | Tanaka, Y | Hydrolase | Hydrolase-hydrolase inhibitor complex | Mmp-13

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of MMP-13 complexed with 4-(2-((6-fluoro-2-((3-methoxybenzyl)carbamoyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid==
 <StructureSection load='3wv1' size='340' side='right' caption='[[3wv1]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </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=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=WHH:4-[2-({6-FLUORO-2-[(3-METHOXYBENZYL)CARBAMOYL]-4-OXO-3,4-DIHYDROQUINAZOLIN-5-YL}OXY)ETHYL]BENZOIC+ACID'>WHH</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">[[3wv2|3wv2]], [[3wv3|3wv3]]</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=3wv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wv1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wv1 RCSB], [http://www.ebi.ac.uk/pdbsum/3wv1 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=3wv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wv1 OCA], [http://pdbe.org/3wv1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wv1 RCSB], [http://www.ebi.ac.uk/pdbsum/3wv1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wv1 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 3wv1" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

3wv1

From Proteopedia

Revision as of 17:21, 9 March 2017

Crystal structure of the catalytic domain of MMP-13 complexed with 4-(2-((6-fluoro-2-((3-methoxybenzyl)carbamoyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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