| Ամփոփում: | Centrioles are key eukaryotic organelles that are responsible
for the formation of cilia and flagella, and for organizing the
microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein
spindle assembly abnormal 6 (SAS-6), which forms a structural
scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal
“head” domains was previously shown to be essential for protein
oligomerization 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 oligomerization. We demonstrate using NMR spectroscopy that a ligand
from this family binds at the head domain dimerization site of
algae, nematode, and human SAS-6 variants, but also that
another ligand specifically recognizes 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 that ligand specificity derives from favorable Van der Waals interactions with a
hydrophobic cavity at the dimerization site.
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