6z4a | pdb_00006z4a

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

spinqualitylabelsall models 6z4a, resolution 1.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6z4a is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SAS6_HUMAN Autosomal recessive primary microcephaly. The disease is caused by variants affecting the gene represented in this entry. Function SAS6_HUMAN Central scaffolding component of the centrioles ensuring their 9-fold symmetry. Required for centrosome biogenesis and duplication: required both for mother-centriole-dependent centriole duplication and deuterosome-dependent centriole amplification in multiciliated cells. Overexpression results in excess foci-bearing centriolar markers. Required for the recruitment of STIL to the procentriole and for STIL-mediated centriole amplification (PubMed:22020124). Publication Abstract from PubMed 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. Identification of compounds that bind the centriolar protein SAS-6 and inhibit its oligomerization.,Busch JMC, Matsoukas MT, Musgaard M, Spyroulias GA, Biggin PC, Vakonakis I J Biol Chem. 2020 Dec 25;295(52):17922-17934. doi: 10.1074/jbc.RA120.014780. Epub , 2020 Sep 1. PMID:32873708 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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