Identification of compounds that bind the centriolar protein SAS-6 and inhibit its oligomerisation

DOI: 10.1074/jbc.RA120.014780

Authors: Julia M. C. Busch (University of Oxford) , Minos-Timotheos Matsoukas (University of Patras) , Maria Musgaard (University of Oxford) , Georgios A. Spyroulias (University of Patras) , Philip C. Biggin (University of Oxford) , Ioannis Vakonakis (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: September 2020
Diamond Proposal Number(s): 12346

Abstract: Centrioles are key eukaryotic organelles responsible for the formation of cilia and flagella, and for organising the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerisation of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organisation of further organelle components. A dimerisation interaction between SAS-6 N-terminal ‘head’ domains was previously shown to be essential for protein oligomerisation in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low molecular weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerisation. We demonstrate using nuclear magnetic resonance spectroscopy that a ligand from this family binds at the head domain dimerisation site of algae, nematode and human SAS-6 variants, but also that another ligand specifically recognises human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest ligand specificity derives from favourable Van der Waals interactions with a hydrophobic cavity at the dimerisation site.

Journal Keywords: ligand design; centrosome; protein-protein interaction; inhibitor; biophysics; nuclear magnetic resonance (NMR)

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Other Facilities: SOLEIL

Added On: 09/09/2020 10:51

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)