Highlights of our Work

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While waste recycling in daily life has become popular only recently, living cells have been recycling their protein content since the very beginning. Recycling of unneeded protein molecules in cells is performed by a molecular machine called the proteasome, which cuts these proteins into smaller pieces for reuse as building blocks for new proteins. Proteins that need to be recycled are labeled by tags made of poly-ubiquitin protein chains. The proteasome machine recognizes and binds to these tags, pulls the tagged protein close, then unwinds it, and finally cuts it into pieces. Despite its substantial role in the cell's life cycle, the proteasome's atomic structure and function still remain elusive. In our recent study, we obtained an atomic structure of the human 26S proteasome by combining computational modeling techniques, through molecular dynamics flexible fitting (MDFF) of the cryo-electron microscopy (cryo-EM) data. The features observed in the resulting structure are important for coordinating the proteasomal subunits during protein recycling. One of the key advances is that for the first time the nucleotides bound to the ATPase motor of the proteasome are resolved. The atomic resolution of the structure permits to perform molecular dynamics simulations to investigate the detailed proteasomal function, in particular the protein unwinding process of the ATPase motor. Furthermore, our obtained structure will serve as a starting point for structure-guided drug discovery, developing the proteasome as a crucial drug target. The atomic models are deposited in the protein data bank (PDB) with the PDB IDs 5L4G and 5L4K and the 3.9 Å resolution cryo-EM density is deposited in the electron microscopy data bank EMD-4002. More information about our proteasome projects is available on our proteasome website. Easy access to our modeling techniques is provided through QwikMD, which was employed here for the first time.