8Q34

Crystal structure of the first bromodomain of human BRD4 in complex with the ligand ZZ001229a

Summary for 8Q34

• Entry DOI: 10.2210/pdb8q34/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, ~{N}-(1~{H}-imidazo[4,5-b]pyridin-2-ylmethyl)-3-(3-methyl-1,2-diazirin-3-yl)propanamide, ... (4 entities in total)
• Functional Keywords: ligand complex, bromodomain, covalent, gene regulation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 63052.41

Authors

MacLean, E.M.,Gao, Q.,Williams, E.,Balcomb, B.H.,von Delft, F.,Bajusz, D.,Keeley, A.,Abranyi-Balogh, P.,Koekemoer, L.,Keseru, G.M. (deposition date: 2023-08-03, release date: 2024-02-07, Last modification date: 2024-08-14)

Primary citation

Abranyi-Balogh, P.,Bajusz, D.,Orgovan, Z.,Keeley, A.B.,Petri, L.,Peczka, N.,Szalai, T.V.,Palfy, G.,Gadanecz, M.,Grant, E.K.,Imre, T.,Takacs, T.,Randelovic, I.,Baranyi, M.,Marton, A.,Schlosser, G.,Ashraf, Q.F.,de Araujo, E.D.,Karancsi, T.,Buday, L.,Tovari, J.,Perczel, A.,Bush, J.T.,Keseru, G.M.
Mapping protein binding sites by photoreactive fragment pharmacophores.
Commun Chem, 7:168-168, 2024

PubMed Abstract: Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRas protein, and the yet unliganded N-terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets.

PubMed: 39085342
DOI: 10.1038/s42004-024-01252-w

Experimental method

X-RAY DIFFRACTION (1.48 Å)