ArticleThe Journal of biological chemistry2010
NMR and bioinformatics discovery of exosites that tune metalloelastase specificity for solubilized elastin and collagen triple helices.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer.Journal of cellular biochemistry · 2017Review
- Thioredoxin fusion construct enables high-yield production of soluble, active matrix metalloproteinase-8 (MMP-8) in Escherichia coli.Protein expression and purification · 2016Article
- Path to Collagenolysis: COLLAGEN V TRIPLE-HELIX MODEL BOUND PRODUCTIVELY AND IN ENCOUNTERS BY MATRIX METALLOPROTEINASE-12.The Journal of biological chemistry · 2016Article
- Matrix metalloproteinases as breast cancer drivers and therapeutic targets.Frontiers in bioscience (Landmark edition) · 2015Review
- Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12.Nature communications · 2014Article
- The role of collagen charge clusters in the modulation of matrix metalloproteinase activity.The Journal of biological chemistry · 2014Article
- Elastin degradation by cathepsin V requires two exosites.The Journal of biological chemistry · 2013Article
- Interstitial collagen catabolism.The Journal of biological chemistry · 2013Review
- Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Remote exosites of the catalytic domain of matrix metalloproteinase-12 enhance elastin degradation.Biochemistry · 2011Article
- Exosite interactions impact matrix metalloproteinase collagen specificities.The Journal of biological chemistry · 2011Article
- Solubilized elastin substrate for continuous fluorimetric assay of kinetics of elastases.Analytical biochemistry · 2011Article
- Matrix metalloproteinase interactions with collagen and elastin.Matrix biology : journal of the International Society for Matrix BiologyReview
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The catalytic domain of metalloelastase (matrix metalloproteinase-12 or MMP-12) is unique among MMPs in exerting high proteolytic activity upon fibrils that resist hydrolysis, especially elastin from lungs afflicted with chronic obstructive pulmonary disease or arteries with aneurysms. How does the MMP-12 catalytic domain achieve this specificity? NMR interface mapping suggests that α-elastin species cover the primed subsites, a strip across the β-sheet from β-strand IV to the II-III loop, and a broad bowl from helix A to helix C. The many contacts may account for the comparatively high affinity, as well as embedding of MMP-12 in damaged elastin fibrils in vivo. We developed a strategy called BINDSIght, for bioinformatics and NMR discovery of specificity of interactions, to evaluate MMP-12 specificity without a structure of a complex. BINDSIght integration of the interface mapping with other ambiguous information from sequences guided choice mutations in binding regions nearer the active site. Single substitutions at each of ten locations impair specific activity toward solubilized elastin. Five of them impair release of peptides from intact elastin fibrils. Eight lesions also impair specific activity toward triple helices from collagen IV or V. Eight sites map to the "primed" side in the III-IV, V-B, and S1' specificity loops. Two map to the "unprimed" side in the IV-V and B-C loops. The ten key residues circumscribe the catalytic cleft, form an exosite, and are distinctive features available for targeting by new diagnostics or therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.