Structure Of Rapamycin’s Target Finally Solved

A plaque commemorating the discovery of Rapamycin on Easter Island

In 2009 everyone was surprised to learn that the drug rapamycin extended the lifespan of mice when started at 600 days of age. For a mice this is middle age and previously everyone had suspected that life extension drugs would only be effective when started early in life. Since, multiple other studies have confirmed that rapamycin extends life in rodents, fruit flies, roundworms, and yeast.  

Rapamycin works by blocking the activity of a protein complex known as mTORC1. mTORC1 plays an essential role in many cellular processes including cell growth, metabolism, autophagy, and survival. Its main function is as an energy and nutrient sensor that tells the cell if the time is right to invest in growth, or alternatively if mechanisms for energy conservation need to be activated. If we look at the hallmarks of aging than we see that mTORC1 is involved in at least five of the nine hallmarks (loss of nutrient sensitivity, loss of proteostasis, cellular senescence, stem cell exhaustion and mitochondrial dysfunction). Hence it’s no surprise that mTORC1 has emerged as an important target in cancer, neurodegeneration and diabetes. 

Credit: Navitor Pharmaceuticals

At the heart of mTORC1 sits a protein known as mTOR (mammalian target of rapamycin). mTOR also forms a second protein complex known as mTORC2. mTOR is a very large protein and when associated with the four other proteins that make up this complex the whole is so big that the study of its structure is very complicated. After 3 years of work the research team succeeded in isolating enough human mTOR associated with two of its binding partners and with rapamycin bound to FKBP for use in a technique known as cryo-electron microscopy. In this technique proteins are poured on a surface cooled to cryogenic temperatures and then studied by an electron microscope. Furthermore the team also used x-ray crystallography to solve the structure of one of the associated proteins known as raptor that they isolated from a fungus. 

The study revealed that the architecture of mTORC1 is quite exceptional. This study helped to explain the role that each of the partner proteins has in regulating the activity of the complex as a whole. Furthermore, this study helps to explain how rapamycin-FKBP binds with mTOR1 to block its activity; an insight that could lead to the development of new drugs (rapalogs) that are more selective for mTORC1 over mTORC2. Such drugs would have fewer, less unpleasant side effects. 

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