Abstract 3053 The intrinsic structural dynamics of a histone deacetylase enzyme dictate enzymatic activity and inhibition

Enzymes are known to sample various conformations, many of which are critical for their biological function. For mutants of a histone deacetylase enzyme (HDAC8), it will be presented that reduced enzymatic activities and reduced inhibitor affinities are all captured by the rate-constants between intrinsically sampled conformations that, in turn, can be obtained independently by solution nuclear magnetic resonance (NMR) spectroscopy. Thus, our findings suggest that changes in enzymatic activity and inhibitor potency are all captured in the differences in the intrinsic enzyme dynamics, and as such, precise structures alone do not adequately explain the effect of missense mutations on enzymatic activity and drug potency.