Crystallographic fragment screening supports tool compound discovery and reveals conformational flexibility in human deoxyhypusine synthase.

ABSTRACT: Deoxyhypusine synthase (DHS) catalyzes the rate-limiting step of hypusination, a unique post-translational modification of eukaryotic translation factor 5 A (eIF5A). While DHS activity plays a critical role in both normal cellular processes and disease development, the lack of specific molecular tools has hindered detailed studies of this enzyme and the hypusination pathway in general. Existing inhibitors, such as polyamine analogs, suffer from limited specificity and versatility. In this study, we utilized crystallographic fragment screening (CFS) to identify potential DHS inhibitors and explore novel applications of this approach. With an unprecedented hit rate of 39%, we identified fragment clusters binding at key sites, including the active site entrance, the tetramer interface, the re

SUBMITTER: Wilk P 

PROVIDER: S-EPMC12868627 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature