| Structural highlights
1hy7 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: | 1g49, 1cqr, 1d5j, 1d7x, 1d8f, 1d8m |
| Gene: | MMP3 (HUMAN) |
| Activity: | Stromelysin 1, with EC number 3.4.24.17 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
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 carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.
Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.,Natchus MG, Bookland RG, Laufersweiler MJ, Pikul S, Almstead NG, De B, Janusz MJ, Hsieh LC, Gu F, Pokross ME, Patel VS, Garver SM, Peng SX, Branch TM, King SL, Baker TR, Foltz DJ, Mieling GE J Med Chem. 2001 Mar 29;44(7):1060-71. PMID:11297453[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, Laufersweiler MJ, Pikul S, Almstead NG, De B, Janusz MJ, Hsieh LC, Gu F, Pokross ME, Patel VS, Garver SM, Peng SX, Branch TM, King SL, Baker TR, Foltz DJ, Mieling GE. Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines. J Med Chem. 2001 Mar 29;44(7):1060-71. PMID:11297453
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