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[[Image:1g49.jpg|left|200px]]<br /><applet load="1g49" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1g49, resolution 1.9&Aring;" />
'''A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3'''<br />


==Overview==
==A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3==
A series of hydroxamates was prepared from an aminoproline scaffold and, tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed, SAR for the series is reported for five enzymes within the MMP family, and, a number of inhibitors, such as compound 47, display broad-spectrum, activity with sub-nanomolar potency for some enzymes. Modifications of the, P1' portion of the molecule played a key role in affecting both potency, and selectivity within the MMP family. Longer-chain aliphatic substituents, in this region of the molecule tended to increase potency for MMP-3 and, decrease potency for MMP-1, as exemplified by compounds 48-50, while, aromatic substituents, as in compound 52, generated broad-spectrum, inhibition. The data is rationalized based upon X-ray crystal data which, is also presented. While the in vitro peroral absorption seemed to be less, predictable, it tended to decrease with longer and more hydrophilic, substituents. Finally, a rat model of osteoarthritis was used to evaluate, the efficacy of these compounds, and a direct link was established between, their pharmacokinetics and their in vivo efficacy.
<StructureSection load='1g49' size='340' side='right'caption='[[1g49]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1g49]] 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=1G49 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1G49 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=111:(1N)-4-N-BUTOXYPHENYLSULFONYL-(2R)-N-HYDROXYCARBOXAMIDO-(4S)-METHANESULFONYLAMINO-PYRROLIDINE'>111</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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=1g49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1g49 OCA], [https://pdbe.org/1g49 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1g49 RCSB], [https://www.ebi.ac.uk/pdbsum/1g49 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1g49 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/g4/1g49_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=1g49 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/>
1G49 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=111:'>111</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1G49 OCA].
__TOC__
 
</StructureSection>
==Reference==
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines., Natchus MG, Bookland RG, De B, Almstead NG, Pikul S, Janusz MJ, Heitmeyer SA, Hookfin EB, Hsieh LC, Dowty ME, Dietsch CR, Patel VS, Garver SM, Gu F, Pokross ME, Mieling GE, Baker TR, Foltz DJ, Peng SX, Bornes DM, Strojnowski MJ, Taiwo YO, J Med Chem. 2000 Dec 28;43(26):4948-63. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11150165 11150165]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Stromelysin 1]]
[[Category: Almstead NG]]
[[Category: Almstead, N.G.]]
[[Category: Bookland RG]]
[[Category: Bookland, R.G.]]
[[Category: De B]]
[[Category: De, B.]]
[[Category: Natchus MG]]
[[Category: Natchus, M.G.]]
[[Category: Pikul S]]
[[Category: Pikul, S.]]
[[Category: 111]]
[[Category: CA]]
[[Category: ZN]]
[[Category: inhibited]]
[[Category: mixed alpha beta structure]]
[[Category: zinc protease]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 15:50:58 2008''

Latest revision as of 10:22, 7 February 2024

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

Structural highlights

1g49 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 1.9Å
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

1g49, resolution 1.90Å

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