[1P-28*] The stability of HSP90NTD and co-chaperone p23 by the domain swapping in HSP90 dimer
Heat Shock Protein 90 (HSP90) has a homodimer and it consists of three domains, NTD, MD, CTD. It forms the close state from the open state when ATP binds. This protein is known as an anti-cancer drug target. In our previous study, we proposed a new peptide drug as a new HSP90 inhibitor. This inhibitor binds to the beta-sheet region of HSP90NTD, and it interacts with the N-terminal region of HSP90NTD. The N-terminal region makes a domain swapping in the close state of the HSP90 dimer. However, the effect of the domain swapping to HSP90 and co-chaperone has been not clear yet. To investigate the importance of domain swapping, we performed several molecular dynamics simulations using the HSP90NTD dimer with and without domain swapping. In the comparison of HSP90NTD dimer, HSP90NTD dimer with ATP, and HSP90NTD dimer with ATP and co-chaperone, we examined the fluctuation of each. As a result, the structures without domain swapping were unstable in all cases, while the structures with domain swapping were stable. Thus it suggests that domain swapping is essential for the stabilization of HSP90. Also, we found that domain swapping is important for the stable binding of the co-chaperone from another simulation.