2jxz

Solution Conformation of A Non-Amyloidogenic Analogue of Human Calcitonin in Sodium Dodecyl Sulfate Micelles

spinqualitylabelsall models 2jxz Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2jxz is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 20 models Ligands: NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 Irreversible aggregation limits bioavailability and therapeutic activity of protein-based drugs. Here we show that an aggregation-resistant mutant can be engineered by structural homology with a non-amyloidogenic analogue, and that the aggregation-resistant variant may act as inhibitor. This strategy has successfully been applied to the amyloidogenic human calcitonin (hCT). Including only five residues from the non-amyloidogenic salmon calcitonin (sCT), we obtained a variant (phCT) whose solution structure was shown, by CD, NMR and calculations, to be practically identical to that of sCT. phCT was also observed to be a potent amylodogenesis inhibitor of hCT when mixed with it in a 1:1 ratio. Fibrillation studies of phCT and phCT-hCT mixture mimic the sCT behavior in the kinetics and shapes of the fibrils, with a dramatic reduction with respect to hCT. Finally, the effect of phCT alone and of the mixture on the intracellular cAMP level in T47D cells confirmed for the mutant and the mixture their calcitonin-like activity, exhibiting stimulation effects identical to those of sCT, the current therapeutic form. The strategy followed appears to be suitable to develop new forms of hCT with a striking reduction of aggregation and improved activity. Finally, the inhibitory properties of the aggregation-resistant analogue, if confirmed for other amyloidogenic peptides, may favor a new strategy for controlling fibril formation in a variety of human diseases. Converting the highly amyloidogenic human calcitonin into a powerful fibril inhibitor by 3D structure homology with a non-amyloidogenic analogue.,Andreotti G, Vitale RM, Avidan-Shpalter C, Amodeo P, Gazit E, Motta A J Biol Chem. 2010 Nov 15. PMID:21078667 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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