5bpa

From Proteopedia

(Difference between revisions)

Revision as of 06:55, 26 July 2016

X-RAY Co-structure of MMP-13 with 4-[({5-[2-(ethoxycarbonyl)-1H-indol-5-yl]-1-methyl-1H-pyrazol-3-yl}formamido)methyl]benzoate

Structural highlights

5bpa is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5boy
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 metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.

Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13.,Taylor SJ, Abeywardane A, Liang S, Muegge I, Padyana AK, Xiong Z, Hill-Drzewi M, Farmer B, Li X, Collins B, Li JX, Heim-Riether A, Proudfoot J, Zhang Q, Goldberg D, Zuvela-Jelaska L, Zaher H, Li J, Farrow NA J Med Chem. 2011 Dec 8;54(23):8174-87. doi: 10.1021/jm201129m. Epub 2011 Nov 9. PMID:22017539^[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
↑ Taylor SJ, Abeywardane A, Liang S, Muegge I, Padyana AK, Xiong Z, Hill-Drzewi M, Farmer B, Li X, Collins B, Li JX, Heim-Riether A, Proudfoot J, Zhang Q, Goldberg D, Zuvela-Jelaska L, Zaher H, Li J, Farrow NA. Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13. J Med Chem. 2011 Dec 8;54(23):8174-87. doi: 10.1021/jm201129m. Epub 2011 Nov 9. PMID:22017539 doi:http://dx.doi.org/10.1021/jm201129m

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/5bpa"

Categories: Farrow, N A | Margarit, S M | Hydrolase-hydrolase inhibitor complex | Protease | Ridgefield

@@ Line 1: / Line 1: @@
 ==X-RAY Co-structure of MMP-13 with 4-[({5-[2-(ethoxycarbonyl)-1H-indol-5-yl]-1-methyl-1H-pyrazol-3-yl}formamido)methyl]benzoate==
 <StructureSection load='5bpa' size='340' side='right' caption='[[5bpa]], [[Resolution|resolution]] 1.79&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=4UF:4-{[({5-[2-(ETHOXYCARBONYL)-1H-INDOL-5-YL]-1-METHYL-1H-PYRAZOL-3-YL}CARBONYL)AMINO]METHYL}BENZOIC+ACID'>4UF</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">[[5boy|5boy]]</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=5bpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bpa OCA], [http://pdbe.org/5bpa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bpa RCSB], [http://www.ebi.ac.uk/pdbsum/5bpa 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=5bpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bpa OCA], [http://pdbe.org/5bpa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bpa RCSB], [http://www.ebi.ac.uk/pdbsum/5bpa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bpa ProSAT]</span></td></tr>
 </table>
 == Disease ==

5bpa

From Proteopedia

Revision as of 06:55, 26 July 2016

X-RAY Co-structure of MMP-13 with 4-[({5-[2-(ethoxycarbonyl)-1H-indol-5-yl]-1-methyl-1H-pyrazol-3-yl}formamido)methyl]benzoate

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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