6Z4A

Structure of the human SAS-6 N-terminal domain, F131E mutant

6Z4A の概要

• エントリーDOI: 10.2210/pdb6z4a/pdb
• 分子名称: Spindle assembly abnormal protein 6 homolog, GLYCEROL (3 entities in total)
• 機能のキーワード: centrosome, centriole, cartwheel, alpha/beta protein, structural protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17837.63

構造登録者

Busch, J.M.C.,Vakonakis, I. (登録日: 2020-05-25, 公開日: 2020-09-09, 最終更新日: 2024-02-07)

主引用文献

Busch, J.M.C.,Matsoukas, M.T.,Musgaard, M.,Spyroulias, G.A.,Biggin, P.C.,Vakonakis, I.
Identification of compounds that bind the centriolar protein SAS-6 and inhibit its oligomerization.
J.Biol.Chem., 295:17922-17934, 2020

PubMed Abstract: 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 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.

PubMed: 32873708
DOI: 10.1074/jbc.RA120.014780

実験手法

X-RAY DIFFRACTION (1.46 Å)