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Comprehensive analysis of binding sites in tubulin

DOI: 10.1002/anie.202100273 DOI Help

Authors: Tobias Muhlethaler (Paul Scherrer Institute (PSI)) , Dario Gioia (Istituto Italiano di Tecnologia) , Andrea Enrico Prota (Paul Scherrer Institute) , May E. Sharpe (Swiss Light Source) , Andrea Cavalli (Istituto Italiano di Tecnologia; University of Bologna) , Michel O. Steinmetz (Paul Scherrer Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 17334

Open Access Open Access

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.

Journal Keywords: crystallographic fragment screening; microtubules

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 10/05/2021 10:28


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening