PDBsum entry 5h1v

Transcription/transcription inhibitor

PDB id: 5h1v

Contents

Protein chains

169 a.a.

Ligands

7FU ×2

DMS

Metals

_ZN ×4

Waters ×143

PDB id:

5h1v

Name:

Transcription/transcription inhibitor

Title:

Complex structure of trim24 phd-bromodomain and inhibitor 6

Structure:

Transcription intermediary factor 1-alpha. Chain: a, b. Fragment: unp residues 824-1006. Synonym: tif1-alpha,e3 ubiquitin-protein ligase trim24,ring finger protein 82,tripartite motif-containing protein 24. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: trim24, rnf82, tif1, tif1a. Expressed in: escherichia coli 'bl21-gold(de3)plyss ag'. Expression_system_taxid: 866768.

Resolution:

2.00Å R-factor: 0.183 R-free: 0.220

Authors:

J.Liu

Key ref:

J.Liu et al. (2017). The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network. Febs J, 284, 1082-1095. PubMed id: 28207202 DOI: 10.1111/febs.14041

Date:

11-Oct-16 Release date: 22-Feb-17

Protein chains

O15164  (TIF1A_HUMAN) -  Transcription intermediary factor 1-alpha from Homo sapiens

Seq: 1050 a.a.

Struc: 169 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

DOI no: 10.1111/febs.14041

Febs J 284:1082-1095 (2017)

PubMed id: 28207202

The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network.

J.Liu, F.Li, H.Bao, Y.Jiang, S.Zhang, R.Ma, J.Gao, J.Wu, K.Ruan.

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.