8fzb | pdb_00008fzb

Crystal structure of human FAM86A

spinqualitylabelsall models 8fzb, resolution 3.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fzb is a 3 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: SAH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EF2KT_HUMAN Catalyzes the trimethylation of eukaryotic elongation factor 2 (EEF2) on 'Lys-525'. Publication Abstract from PubMed FAM86A is a class I lysine methyltransferase (KMT) that generates trimethylation on the eukaryotic translation elongation factor 2 (EEF2) at Lys525. Publicly available data from The Cancer Dependency Map project indicate high dependence of hundreds of human cancer cell lines on FAM86A expression. This classifies FAM86A among numerous other KMTs as potential targets for future anticancer therapies. However, selective inhibition of KMTs by small molecules can be challenging due to high conservation within the S-adenosyl methionine (SAM) cofactor binding domain among KMT subfamilies. Therefore, understanding the unique interactions within each KMT-substrate pair can facilitate developing highly specific inhibitors. The FAM86A gene encodes an N-terminal FAM86 domain of unknown function in addition to its C-terminal methyltransferase domain. Here, we used a combination of X-ray crystallography, the AlphaFold algorithms, and experimental biochemistry to identify an essential role of the FAM86 domain in mediating EEF2 methylation by FAM86A. To facilitate our studies, we also generated a selective EEF2K525 methyl antibody. Overall, this is the first report of a biological function for the FAM86 structural domain in any species and an example of a noncatalytic domain participating in protein lysine methylation. The interaction between the FAM86 domain and EEF2 provides a new strategy for developing a specific FAM86A small molecule inhibitor, and our results provide an example in which modeling a protein-protein interaction with AlphaFold expedites experimental biology. The FAM86 domain of FAM86A confers substrate specificity to promote EEF2-Lys525 methylation.,Francis JW, Shao Z, Narkhede P, Trinh AT, Lu J, Song J, Gozani O J Biol Chem. 2023 May 18;299(7):104842. doi: 10.1016/j.jbc.2023.104842. PMID:37209825 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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