************第３５回尾張コンプレックスセミナー*************

Title　：　A pharmacological chaperone regulating the conformation of prion
 protein

Speaker ：　Norifumi Yamamoto

Affiliation：　Division of Prion Research, Center for Emerging Infectious
 Diseases, Gifu University

Date　：　Wed. Mar. 31th, 2:00 pm (Almost one hour)

Place　：　Room 616, Graduate School of Information Science

Abstract：
Prion diseases result from the conformational conversion of a normal prion
protein (PrPC) into an abnormal isoform (PrPSc). Recently, we discovered
an anti-prion compound GN8 to interfere with the pathological conversion
of prion protein; however, the mechanisms underlying the anti-prion
activity remained unresolved. In this study, we provide the first evidence
in supporting the chemical chaperone hypothesis that GN8 acts as a
chaperone to stabilize the normal form of PrPC. We performed a
comparative study between different conformations of PrPC with and
without GN8 binding based on molecular dynamics (MD) simulations. We
employed urea-driven unfolding simulations to determine if GN8 prevented
the conformational conversion of PrPC. One important finding was that GN8
efficiently suppresses local fluctuations and prevent for the partial
unfoldingof PrPC under denaturing perturbation. We concluded that GN8 inhibits 
the pathological conversion of PrPC to PrPSc by suppressing the population of
the intermediate state of PrP*. Our basic principle presented in this study
constitutes a promising strategy with which to approach a dynamic-based
drug design of therapeutic chemical chaperones, i.e., pharmacological
chaperones, for conformational diseases related to protein misfolding.
[N. Yamamoto and K. Kuwata, J. Phys. Chem. B, 113, 12853 (2009)]

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