Comprehensive Analysis of Binding Sites in Tubulin. (5th May 2021)

• Record Type: Journal Article
• Authors: Mühlethaler, Tobias; Gioia, Dario; Prota, Andrea E.; Sharpe, May E.; Cavalli, Andrea; Steinmetz, Michel O.
• Is Part Of: Angewandte Chemie. Volume 133:Number 24(2021)
• Page Start: 13443
• Page End: 13454
• Publication Date: 2021-05-05
• Subjects: crystallographic fragment screening -- microtubules -- molecular dynamics simulation -- protein–ligand interactions -- tubulin; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202100273
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and crystallographic fragment screening approach, we addressed the question of how many binding sites exist in tubulin. We identified 27 distinct sites, of which 11 have not been described previously, and analyzed their relationship to known tubulin–protein and tubulin–ligand interactions. We further observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. Our results offer a unique structural basis for the development of novel small molecules for use as tubulin modulators in basic research applications or as drugs. Furthermore, our method lays down a framework that may help to discover new pockets in other pharmaceutically important targets and characterize them in terms of chemical tractability and allosteric modulation. Abstract : How many binding sites exist in the vital anticancer protein target tubulin? A combined computational and crystallographic fragment screening approach now answers this question and reveals 11 novel sites as well as 56 novel small‐molecule ligands in tubulin.