Abstract 2460 Structure Studies of Suicide Inhibitors Bound to Human Pin1

Human Pin1 (= protein interacting with NIMA (never in mitosis A)-1) catalyzes the cis/trans isomerization of the peptide bond between phosphorylated Serine/Threonine and Proline. This isomerization reaction is critical to many physiological processes in the cell. Aberrations of the activity or of the expression level of Pin1 are implicated in the development of many diseases. A deficiency or inactivation of Pin1 may cause Alzheimer's disease, as Pin1 promotes the degradation of Tau. An overexpression of Pin1 is related to the malignancy of cancers, as it controls many oncogenes and tumor suppressors. Thus, inhibitors of Pin1 have been developed as anticancer drugs. Here, we present our structure studies of the binding of newly developed anticancer drugs bound to hPin1, to further improve their efficacy. Our structures reveal a new mechanism in which the bound inhibitor destabilizes hPin1, causing a structural change that leads to hPin1 degradation in cellulo. We propose that other inhibitors that have been previously dismissed because they destabilized the structure of their target protein may also induce a structural change that leads to degradation in cellulo. This research was funded by NIH grants NS107479 (to MP), CA168517 (to MP), and CA285114 (to MP and GB). MP holds the Daniel Hays Chair in Cancer Research at the School of Medicine at UCR.