This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

1you

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 08:49, 20 January 2021

Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor

Structural highlights

1you 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:	, , ,
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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.

Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14.,Blagg JA, Noe MC, Wolf-Gouveia LA, Reiter LA, Laird ER, Chang SP, Danley DE, Downs JT, Elliott NC, Eskra JD, Griffiths RJ, Hardink JR, Haugeto AI, Jones CS, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robinson RP, Subramanyam C, Vaughn-Bowser ML, Yocum SA Bioorg Med Chem Lett. 2005 Apr 1;15(7):1807-10. PMID:15780611^[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
↑ Blagg JA, Noe MC, Wolf-Gouveia LA, Reiter LA, Laird ER, Chang SP, Danley DE, Downs JT, Elliott NC, Eskra JD, Griffiths RJ, Hardink JR, Haugeto AI, Jones CS, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robinson RP, Subramanyam C, Vaughn-Bowser ML, Yocum SA. Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14. Bioorg Med Chem Lett. 2005 Apr 1;15(7):1807-10. PMID:15780611 doi:10.1016/j.bmcl.2005.02.038

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1you"

Categories: Human | Large Structures | Pandit, J | Hydrolase | Metalloprotease

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor==
-<StructureSection load='1you' size='340' side='right' caption='[[1you]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='1you' size='340' side='right'caption='[[1you]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1you]] 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=1YOU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1YOU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1you]] 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=1YOU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1YOU 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=PFD:5-(2-ETHOXYETHYL)-5-[4-(4-FLUOROPHENOXY)PHENOXY]PYRIMIDINE-2,4,6(1H,3H,5H)-TRIONE'>PFD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PFD:5-(2-ETHOXYETHYL)-5-[4-(4-FLUOROPHENOXY)PHENOXY]PYRIMIDINE-2,4,6(1H,3H,5H)-TRIONE'>PFD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=1you FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1you OCA], [http://pdbe.org/1you PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1you RCSB], [http://www.ebi.ac.uk/pdbsum/1you PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1you 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=1you FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1you OCA], [http://pdbe.org/1you PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1you RCSB], [http://www.ebi.ac.uk/pdbsum/1you PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1you ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 33: / Line 33: @@
 ==See Also==
-*[[Matrix metalloproteinase|Matrix metalloproteinase]]
+*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
 == References ==
 <references/>
@@ Line 39: / Line 39: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Pandit, J]]
 [[Category: Hydrolase]]
 [[Category: Metalloprotease]]

1you

From Proteopedia

Revision as of 08:49, 20 January 2021

Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox