Related ArticlesPotent ?-secretase inhibitors/modulators interact with Amyloid-? fibrils but do not inhibit fibrillation: A high-resolution NMR study.
Biochem Biophys Res Commun. 2014 Apr 16;
Authors: Yesuvadian R, Krishnamoorthy J, Ramamoorthy A, Bhunia A
Abstract
Recently, ?-secretase modulators (GSM) have been shown to interact directly with the amyloid precursor protein (APP) and simultaneously inhibit the activity of the Presenilin domain of ?-secretase. A clear understanding of the molecular recognition pathways by which GSM can target both ?-secretase and A? precursor protein can lead to the development of more effective inhibitors. To examine whether this direct interaction with APP affects the downstream A? fibril formation, we chose to investigate three different molecules in this study: Sulindac sulfide, Segmacestat and E2012 from the class of generation I GSMs, ?-secretase inhibitors (GSI), and generation II GSM molecules, respectively. Firstly, through NMR based ligand titration, we identified that Sulindac Sulfide and Segmacestat interact strongly with A?40 monomers, whereas E2012 does not. Secondly, using saturation transfer difference (STD) NMR experiments, we found that all three molecules bind equally well with A?40 fibrils. To determine if these interactions with the monomer/fibril lead to a viable inhibition of the fibrillation process, we designed an NMR based time-dependent assay and accurately distinguished the inhibitors from the non-inhibitors within a short period of 12 hours. Based on this pre-seeded fibril assay, we conclude that none of these molecules inhibit the ongoing fibrillation, rather ligands such as Semagacestat and E2012 accelerated the rate of aggregation.
PMID: 24747079 [PubMed - as supplied by publisher]
Sensitive 13Câ??13C correlation spectra of amyloid fibrils at very high spinning frequencies and magnetic fields
Sensitive 13Câ??13C correlation spectra of amyloid fibrils at very high spinning frequencies and magnetic fields
Abstract Sensitive 2D solid-state 13Câ??13C correlation spectra of amyloid β fibrils have been recorded at very fast spinning frequencies and very high magnetic fields. It is demonstrated that PARIS-xy recoupling using moderate rf amplitudes can provide structural information by promoting efficient magnetization transfer even under such challenging experimental conditions. Furthermore, it has been shown both experimentally and by numerical simulations that the method is not...
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Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy.
Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy.
Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy.
J Am Chem Soc. 2010 Oct 6;132(39):13765-75
Authors: Van Melckebeke H, Wasmer C, Lange A, Ab E, Loquet A, Böckmann A, Meier BH
We present a strategy to solve the high-resolution structure of amyloid fibrils by solid-state NMR and use it to determine the atomic-resolution structure of the prion domain of the fungal prion HET-s...
[NMR paper] High-resolution molecular structure of a peptide in an amyloid fibril determined by m
High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy.
Related Articles High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy.
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):711-6
Authors: Jaroniec CP, MacPhee CE, Bajaj VS, McMahon MT, Dobson CM, Griffin RG
Amyloid fibrils are self-assembled filamentous structures associated with protein deposition conditions including Alzheimer's disease and the transmissible...
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[NMR paper] Probing solvent accessibility of amyloid fibrils by solution NMR spectroscopy.
Probing solvent accessibility of amyloid fibrils by solution NMR spectroscopy.
Related Articles Probing solvent accessibility of amyloid fibrils by solution NMR spectroscopy.
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8648-53
Authors: Ippel JH, Olofsson A, Schleucher J, Lundgren E, Wijmenga SS
Amyloid is the result of an anomalous protein and peptide aggregation, leading to the formation of insoluble fibril deposits. At present, 18 human diseases have been associated with amyloid deposits-e.g., Alzheimer's disease and Prion-transmissible...
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Atomic-Resolution Three-Dimensional Structure of HET-s(218-289) Amyloid Fibrils by So
Atomic-Resolution Three-Dimensional Structure of HET-s(218-289) Amyloid Fibrils by Solid-State NMR Spectroscopy
He?le?ne Van Melckebeke, Christian Wasmer, Adam Lange, Eiso AB, Antoine Loquet, Anja Bo?ckmann and Beat H. Meier
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/0/jacsat.ahead-of-print/ja104213j/aop/images/medium/ja-2010-04213j_0001.gif
Journal of the American Chemical Society
DOI: 10.1021/ja104213j
http://feeds.feedburner.com/~ff/acs/jacsat?d=yIl2AUoC8zA
http://feeds.feedburner.com/~r/acs/jacsat/~4/qGRhA6CtOVc
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09-10-2010 12:48 AM
High-Resolution MAS NMR Analysis of PI3-SH3 Amyloid Fibrils: Backbone Conformation an
High-Resolution MAS NMR Analysis of PI3-SH3 Amyloid Fibrils: Backbone Conformation and Implications for Protofilament Assembly and Structure
http://pubs.acs.org//appl/literatum/publisher/achs/journals/content/bichaw/0/bichaw.ahead-of-print/bi100864t/aop/images/medium/bi-2010-00864t_0004.gifBiochemistry, Volume 0, Issue 0, Articles ASAP (As Soon As Publishable).
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High-Resolution MAS NMR Analysis of PI3-SH3 Amyloid Fibrils: Backbone Conformation an
High-Resolution MAS NMR Analysis of PI3-SH3 Amyloid Fibrils: Backbone Conformation and Implications for Protofilament Assembly and Structure .
Related Articles High-Resolution MAS NMR Analysis of PI3-SH3 Amyloid Fibrils: Backbone Conformation and Implications for Protofilament Assembly and Structure .
Biochemistry. 2010 Aug 13;
Authors: Bayro MJ, Maly T, Birkett NR, Macphee CE, Dobson CM, Griffin RG
The SH3 domain of the PI3 kinase (PI3-SH3 or PI3K-SH3) readily aggregates into fibrils in vitro and has served as an important model system in the...
Potent ?-secretase inhibitors/modulators interact with Amyloid-? fibrils but do not inhibit fibrillation: A high-resolution NMR study.
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