[The insulin receptor discovery is 50 years old - A review of achieved progress].

Abstract

The isolation of insulin from the pancreas and its purification to a degree permitting its safe administration to type 1 diabetic patients were accomplished 100 years ago at the University of Toronto by Banting, Best, Collip and McLeod and constitute undeniably one of the major medical therapeutic revolutions, recognized by the attribution of the 1923 Nobel Prize in Physiology or Medicine to Banting and McLeod. The clinical spin off was immediate as well as the internationalization of insulin's commercial production. The outcomes regarding basic research were much slower, in particular regarding the molecular mechanisms of insulin action on its target cells. It took almost a half-century before the determination of the tri-dimensional structure of insulin in 1969 and the characterization of its cell receptor in 1970-1971. The demonstration that the insulin receptor is in fact an enzyme named tyrosine kinase came in the years 1982-1985, and the crystal structure of the intracellular kinase domain 10 years later. The crystal structure of the first intracellular kinase substrate (IRS-1) in 1991 paved the way for the elucidation of the intracellular signalling pathways but it took 15 more years to obtain the complete crystal structure of the extracellular receptor domain (without insulin) in 2006. Since then, the determination of the structure of the whole insulin-receptor complex in both the inactive and activated states has made considerable progress, not least due to recent improvement in the resolution power of cryo-electron microscopy. I will here review the steps in the development of the concept of hormone receptor, and of our knowledge of the structure and molecular mechanism of activation of the insulin receptor.