6v9t | pdb_00006v9t

Tudor domain of TDRD3 in complex with a small molecule

spinqualitylabelsall models 6v9t, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6v9t is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.154Å Ligands: 36X, UNX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TDRD3_HUMAN Scaffolding protein that specifically recognizes and binds dimethylarginine-containing proteins. In nucleus, acts as a coactivator: recognizes and binds asymmetric dimethylation on the core histone tails associated with transcriptional activation (H3R17me2a and H4R3me2a) and recruits proteins at these arginine-methylated loci. In cytoplasm, may play a role in the assembly and/or disassembly of mRNA stress granules and in the regulation of translation of target mRNAs by binding Arg/Gly-rich motifs (GAR) in dimethylarginine-containing proteins. Publication Abstract from PubMed Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A, resulting in transcription termination and R-loop accumulation mimicking SMN depletion. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN. A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II.,Liu Y, Iqbal A, Li W, Ni Z, Wang Y, Ramprasad J, Abraham KJ, Zhang M, Zhao DY, Qin S, Loppnau P, Jiang H, Guo X, Brown PJ, Zhen X, Xu G, Mekhail K, Ji X, Bedford MT, Greenblatt JF, Min J Nat Commun. 2022 Sep 16;13(1):5453. doi: 10.1038/s41467-022-33229-5. PMID:36114190 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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