title: The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network.
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.
  
  
  
  Structural data are available in the PDB under the accession numbers 5H1T, 5H1U, and 5H1V.
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Jiuyang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Fudong
authors.initials: F
authors.lastname: Li
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Bao
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Shuya
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Rongsheng
authors.initials: R
authors.lastname: Ma
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Gao
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors.forename: Ke
authors.identifier: 0000-0001-9358-0451
authors.initials: K
authors.lastname: Ruan
mesh_terms: D020816:Amino Acid Motifs; D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
chemical_list: D001562:Benzimidazoles; D002352:Carrier Proteins; D008024:Ligands; D011994:Recombinant Proteins; C555317:TRIM24 protein, human; D014867:Water
keywords: NMR fragment-based lead discovery; TRIM24 bromodomain inhibitor; epigenetics; protein-ligand complex structure; protein-protein interaction inhibitor