1g49

From Proteopedia

(Difference between revisions)

Revision as of 07:29, 19 June 2019

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

Structural highlights

1g49 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:	, ,
Related:	1cqr, 1d5j, 1d7x, 1d8f, 1d8m, 1g05
Gene:	MMP3 (HUMAN)
Activity:	Stromelysin 1, with EC number 3.4.24.17
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.

Publication Abstract from PubMed

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.

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:11150165^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ 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
↑ 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. Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines. J Med Chem. 2000 Dec 28;43(26):4948-63. PMID:11150165

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/1g49"

@@ Line 1: / Line 1: @@
 ==A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3==
-<StructureSection load='1g49' size='340' side='right' caption='[[1g49]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<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. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1G49 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1g49]] 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=1G49 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1G49 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cqr|1cqr]], [[1d5j|1d5j]], [[1d7x|1d7x]], [[1d8f|1d8f]], [[1d8m|1d8m]], [[1g05|1g05]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MMP3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </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=1g49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1g49 OCA], [http://pdbe.org/1g49 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1g49 RCSB], [http://www.ebi.ac.uk/pdbsum/1g49 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1g49 ProSAT]</span></td></tr>
@@ Line 17: / Line 18: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g4/1g49_consurf.spt"</scriptWhenChecked>
+    <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>
@@ Line 39: / Line 40: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Stromelysin 1]]
 [[Category: Almstead, N G]]

1g49

From Proteopedia

Revision as of 07:29, 19 June 2019

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

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