1d5j: Difference between revisions

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New page: left|200px<br /> <applet load="1d5j" size="450" color="white" frame="true" align="right" spinBox="true" caption="1d5j, resolution 2.6Å" /> '''CRYSTAL STRUCTURE OF...
 
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[[Image:1d5j.gif|left|200px]]<br />
<applet load="1d5j" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1d5j, resolution 2.6&Aring;" />
'''CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.'''<br />


==Overview==
==CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.==
The synthesis and enzyme inhibition data for a series of thiazine- and, thiazepine-based matrix metalloproteinase (MMP) inhibitors are described., The thiazine- and thiazepine-based inhibitors were discovered by, optimization of hetererocyclic sulfonamide-based inhibitors. The most, potent series of inhibitors was obtained by modification of the amino acid, D-penicillamine. This amino acid provides a gem-dimethyl group on the, thiazine or thiazepine ring which has a dramatic effect on the in vitro, potency of this series. In particular, the sulfide 4a and the sulfone 5a, were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against, MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel, thiazepine-based series of MMP inhibitors was established based on X-ray, crystallography of the complex of stromelysin and 4a.
<StructureSection load='1d5j' size='340' side='right'caption='[[1d5j]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1d5j]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D5J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D5J FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</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=MM3:N-HYDROXY-4-[(4-METHOXYLPHENYL)SULFONYL]-2,2-DIMETHYL-HEXAHYDRO-1,4-THIAZEPINE-3(S)-CARBOXAMIDE'>MM3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1d5j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d5j OCA], [https://pdbe.org/1d5j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d5j RCSB], [https://www.ebi.ac.uk/pdbsum/1d5j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d5j ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN] Defects in MMP3 are the cause of susceptibility to coronary heart disease type 6 (CHDS6) [MIM:[https://omim.org/entry/614466 614466]. A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. Note=A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions.<ref>PMID:8662692</ref> <ref>PMID:12477941</ref>
== Function ==
[https://www.uniprot.org/uniprot/MMP3_HUMAN MMP3_HUMAN] Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d5/1d5j_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1d5j ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=185250 185250]]
*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1D5J is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with ZN, CA and MM3 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1D5J OCA].
__TOC__
 
</StructureSection>
==Reference==
[[Category: Homo sapiens]]
Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors., Almstead NG, Bradley RS, Pikul S, De B, Natchus MG, Taiwo YO, Gu F, Williams LE, Hynd BA, Janusz MJ, Dunaway CM, Mieling GE, J Med Chem. 1999 Nov 4;42(22):4547-62. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10579818 10579818]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Almstead NG]]
[[Category: Stromelysin 1]]
[[Category: Bradley RS]]
[[Category: Almstead, N.G.]]
[[Category: De B]]
[[Category: Bradley, R.S.]]
[[Category: Natchus MG]]
[[Category: De, B.]]
[[Category: Pikul S]]
[[Category: Natchus, M.G.]]
[[Category: Pikul, S.]]
[[Category: CA]]
[[Category: MM3]]
[[Category: ZN]]
[[Category: inhibited]]
[[Category: mixed alpha beta structure]]
[[Category: zinc protease]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:29:13 2007''

Latest revision as of 09:49, 7 February 2024

CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.

Structural highlights

1d5j is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.6Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MMP3_HUMAN Defects in MMP3 are the cause of susceptibility to coronary heart disease type 6 (CHDS6) [MIM:614466. A multifactorial disease characterized by an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. Decreased capacity of the coronary vessels is often associated with thickening and loss of elasticity of the coronary arteries. Note=A polymorphism in the MMP3 promoter region is associated with the risk of coronary heart disease and myocardial infarction, due to lower MMP3 proteolytic activity and higher extracellular matrix deposition in atherosclerotic lesions.[1] [2]

Function

MMP3_HUMAN Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.

Evolutionary Conservation

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

See Also

References

  1. ↑ Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996 May 31;271(22):13055-60. PMID:8662692
  2. ↑ Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tanaka M, Yokota M. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002 Dec 12;347(24):1916-23. PMID:12477941 doi:10.1056/NEJMoa021445

1d5j, resolution 2.60Å

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