TY - JOUR T1 - Dynamically-Driven Inactivation of the Catalytic Machinery of the SARS 3C-Like Protease by the N214A Mutation on the Extra Domain A1 - Shi, Jiahai A1 - Han, Nanyu A1 - Lim, Liangzhong A1 - Lua, Shixiong A1 - Sivaraman, J. A1 - Wang, Lushan A1 - Mu, Yuguang A1 - Song, Jianxing Y1 - 2011/02/24 N2 - Author Summary Severe acute respiratory syndrome (SARS) is the first emerging infectious disease of the 21st century which has not only caused rapid infection and death, but also triggered a dramatic social crisis. Its 3C-like protease is crucial for reproducing virus and thus represents a top target for drug design. Interestingly, unlike 3C protease such as from picorovirus, the SARS protease evolutionarily acquired a C-terminal extra domain with previously-unknown function. Immediately after SARS outbreak, we revealed that the extra domain was able to regulate the catalysis by controlling the dimerization essential for activity. Here, we studied one mutant with only slightly-weakened dimerization but almost completely abolished activity. We determined its three-dimensional structure but very unexpectedly it is almost identical to that of the wild-type enzyme. Therefore, we initiated 30-ns molecular dynamic simulations for five forms of the enzyme and the results demonstrate that the dynamical changes in this mutant are responsible for its inactivation. Therefore, the extra domain can also control the catalysis by modulating the enzyme dynamics. This is not only of fundamental significance to understanding how enzymes evolve, but also implies a novel avenue for design of anti-SARS molecules. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 7 IS - 2 UR - https://doi.org/10.1371/journal.pcbi.1001084 SP - e1001084 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1001084 ER -