5yj8 | pdb_00005yj8
Identification of a small molecule inhibitor for the Tudor domain of TDRD3
Structural highlights
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.[1] [2] [3] Publication Abstract from PubMedAs a reader of di-methylated arginine on various proteins, such as histone, RNA polymerase II, PIWI and Fragile X mental retardation protein, the Tudor domain of Tudor domain-containing protein 3 (TDRD3) mediates transcriptional activation in nucleus and formation of stress granules in the cytoplasm. Despite the TDRD3 implication in cancer cell proliferation and invasion, warheads to block the di-methylated arginine recognition pocket of the TDRD3 Tudor domain have not yet been uncovered. Here we identified 14 small molecule hits against the TDRD3 Tudor domain through NMR fragment-based screening. These hits were further cross-validated by using competitive fluorescence polarization and isothermal titration calorimetry experiments. The crystal structure of the TDRD3 Tudor domain in complex with hit 1 reveals a distinct binding mode from the nature substrate. Hit 1 protrudes into the aromatic cage of the TDRD3 Tudor domain, where the aromatic residues are tilted to accommodate a sandwich-like pi-pi interaction. The side chain of the conserved residue N596 swings away 3.1 A to form a direct hydrogen bond with hit 1. Moreover, this compound shows a decreased affinity against the single Tudor domain of survival motor neuron protein, but no detectable binding to neither the tandem Tudor domain of TP53-binding protein 1 nor the extended Tudor domain of staphylococcal nuclease domain-containing protein 1. Our work depicts the structural plasticity of the TDRD3 Tudor domain and paves the way for the subsequent structure-guided discovery of selective inhibitors targeting Tudor domains. DATABASE: Structural data are available in the PDB under the accession number 5YJ8. Structural plasticity of the TDRD3 Tudor domain probed by a fragment screening hit.,Liu J, Zhang S, Liu M, Liu Y, Nshogoza G, Gao J, Ma R, Yang Y, Wu J, Zhang J, Li F, Ruan K FEBS J. 2018 Apr 12. doi: 10.1111/febs.14469. PMID:29645362[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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