Molecular chaperones discovery

The complexity of regulation of Raf kinase was shown by the discovery of a further three proteins which can specifically associate with Raf kinase (review Morrison and Cutler, 1997, Sternberg and Alberola-Ila, 1998). Members of the family of 14-3-3 proteins are found associated with Raf kinase. The 14-3-3 proteins recognize and bind phosphoserine residues in a particular sequence environment. It is assumed that the 14-3-3 proteins bind to Ser-phosphate residues of Raf kinase and thereby fix it in an inactive conformation. Other Raf-interacting proteins include the molecular chaperones hsp90 and p50. These proteins appear to be important for maintaining protein stability and for the proper localization of Raf kinase within the cell. 

The history of study of molecular chaperones is rather fascinating and merits at least a brief review. The initial discovery that heat shock was able to modify gene expression was made... 

Woodhead AJ et al (2010) Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpi-perazin-l-ylmethyl)-l,3-di hydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem 53(16) 5956-5969... 

Inhibitors of Molecular Chaperones as Therapeutic Agents 38 Orphan Drugs and Rare Diseases 39 Ion Channel Drug Discovery 40 Macrocycles in Drug Discovery 41 Human-based sterns for Translational Research 42 Venoms to Drugs Venom as a Source for the Development of Human Therapeutics... 

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