5H1U

Complex structure of TRIM24 PHD-bromodomain and inhibitor 2

Summary for 5H1U

• Entry DOI: 10.2210/pdb5h1u/pdb
• Related: 5H1T 5H1V
• Descriptor: Transcription intermediary factor 1-alpha, 2-amino-1,3-benzothiazole-6-carboxamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: transcription transcription inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : O15164
• Total number of polymer chains: 4
• Total formula weight: 86455.84

Authors

Liu, J. (deposition date: 2016-10-11, release date: 2017-02-22, Last modification date: 2023-11-08)

Primary citation

Liu, J.,Li, F.,Bao, H.,Jiang, Y.,Zhang, S.,Ma, R.,Gao, J.,Wu, J.,Ruan, K.
The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network
FEBS J., 284:1082-1095, 2017

PubMed Abstract: Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors. Interestingly, the polar substitution on the warhead of one new inhibitor pulls the whole ligand approximately 2 Å into the inner side pocket of the TRIM24 bromodomain, and thus exhibits a binding mode significantly different from other known bromodomain ligands. This mode provides a useful handle for further hit-to-lead evolution toward novel inhibitors of the TRIM24 bromodomain.

PubMed: 28207202
DOI: 10.1111/febs.14041

Experimental method

X-RAY DIFFRACTION (1.901 Å)