Structural and mechanistic investigations of the spliceosome

Shi's group has been focusing on the structural and mechanistic elucidation of pre-mRNA splicing in the past decades. After the success of crystal structural elucidation of subcomplexes within spliceosome, they took a direct assault on the intact spliceosome and made the breakthrough in the summer of 2015. They determined the structure of intron lariat spliceosome ILS complex from S. pombe at an average resolution of 3.6 angstrom, which is the first atomic structure of the intact spliceosome, revealing the organization of the spliceosomal components and the conformation of the splicing active site for the first time in the world. Since then, Dr. Shi's group has reported the high-resolution structures of the spliceosome in all eight major fully-assembled functional states, as well as the structure of the largest pre-assembled subcomplex U4/U6.U5 tri-snRNP from S. cerevisiae. The ten structures give rise to a complete structural view for spliceosome activation, catalysis and disassembly. His group also captured 7 key intermediates of human spliceosome, providing structural basis of the evolution of the spliceosome machinery from lower to higher eukaryotes. Taken together, these accomplishments represent a major contribution in this field, which conceptionally advance our understanding to the molecular mechanism of pre-mRNA splicing and provide unprecedented insights into the research on pathogenesis of related diseases and drug discovery.