5YJ8

Identification of a small molecule inhibitor for the Tudor domain of TDRD3

Summary for 5YJ8

• Entry DOI: 10.2210/pdb5yj8/pdb
• Descriptor: Tudor domain-containing protein 3, 5-(aminomethyl)-1,3-dimethyl-benzimidazol-2-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transcriptional coactivator, complex, inhibitor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 7434.38

Authors

Liu, J.,Ruan, K. (deposition date: 2017-10-09, release date: 2018-05-02, Last modification date: 2023-11-22)

Primary citation

Liu, J.,Zhang, S.,Liu, M.,Liu, Y.,Nshogoza, G.,Gao, J.,Ma, R.,Yang, Y.,Wu, J.,Zhang, J.,Li, F.,Ruan, K.
Structural plasticity of the TDRD3 Tudor domain probed by a fragment screening hit.
FEBS J., 285:2091-2103, 2018

PubMed Abstract: As 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 π-π interaction. The side chain of the conserved residue N596 swings away 3.1 Å 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.

PubMed: 29645362
DOI: 10.1111/febs.14469

Experimental method

X-RAY DIFFRACTION (1.762 Å)