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5uwl

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Revision as of 08:25, 30 September 2020

Matrix metalloproteinase-13 complexed with selective inhibitor compound (S)-17a

Structural highlights

5uwl is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5uwk, 5uwm, 5uwn
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

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13.inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.,Choi JY, Fuerst R, Knapinska AM, Taylor AB, Smith L, Cao X, Hart PJ, Fields GB, Roush WR J Med Chem. 2017 Jul 13;60(13):5816-5825. doi: 10.1021/acs.jmedchem.7b00514. Epub, 2017 Jun 27. PMID:28653849^[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
↑ Choi JY, Fuerst R, Knapinska AM, Taylor AB, Smith L, Cao X, Hart PJ, Fields GB, Roush WR. Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors. J Med Chem. 2017 Jul 13;60(13):5816-5825. doi: 10.1021/acs.jmedchem.7b00514. Epub, 2017 Jun 27. PMID:28653849 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00514

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/5uwl"

@@ Line 1: / Line 1: @@
 ==Matrix metalloproteinase-13 complexed with selective inhibitor compound (S)-17a==
-<StructureSection load='5uwl' size='340' side='right' caption='[[5uwl]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
+<StructureSection load='5uwl' size='340' side='right'caption='[[5uwl]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5uwl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UWL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UWL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5uwl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UWL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UWL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8OJ:(S)-N-(3-methyl-1-(methylamino)-1-oxobutan-2-yl)-5-(4-(((4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)thio)methyl)phenyl)furan-2-carboxamide'>8OJ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8OJ:(S)-N-(3-methyl-1-(methylamino)-1-oxobutan-2-yl)-5-(4-(((4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)thio)methyl)phenyl)furan-2-carboxamide'>8OJ</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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">[[5uwk|5uwk]], [[5uwm|5uwm]], [[5uwn|5uwn]]</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=5uwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uwl OCA], [http://pdbe.org/5uwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uwl RCSB], [http://www.ebi.ac.uk/pdbsum/5uwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uwl ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5uwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uwl OCA], [http://pdbe.org/5uwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uwl RCSB], [http://www.ebi.ac.uk/pdbsum/5uwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uwl ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 5uwl" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Cao, X]]
 [[Category: Hart, P J]]

5uwl

From Proteopedia

Revision as of 08:25, 30 September 2020

Matrix metalloproteinase-13 complexed with selective inhibitor compound (S)-17a

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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