5MQE

Crystal structure of CREBBP bromodomain complexed with CBP006

Summary for 5MQE

• Entry DOI: 10.2210/pdb5mqe/pdb
• Descriptor: CREB-binding protein, 4-bromanyl-~{N}-methyl-1~{H}-pyrrole-2-carboxamide (3 entities in total)
• Functional Keywords: crebbp bromodomain, inhibitor, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28852.77

Authors

Zhu, J.,Spiliotopoulos, D.,Caflisch, A. (deposition date: 2016-12-20, release date: 2017-04-19, Last modification date: 2024-05-08)

Primary citation

Spiliotopoulos, D.,Zhu, J.,Wamhoff, E.C.,Deerain, N.,Marchand, J.R.,Aretz, J.,Rademacher, C.,Caflisch, A.
Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.
Bioorg. Med. Chem. Lett., 27:2472-2478, 2017

PubMed Abstract: Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in a variety of cellular processes, has been observed in several types of cancer with a correlation to aggressiveness. We have screened a library of nearly 1500 fragments by high-throughput docking into the CBP bromodomain followed by binding energy evaluation using a force field with electrostatic solvation. Twenty of the 39 fragments selected by virtual screening are positive in one or more ligand-observed nuclear magnetic resonance (NMR) experiments. Four crystal structures of the CBP bromodomain in complex with in silico screening hits validate the pose predicted by docking. Thus, the success ratio of the high-throughput docking procedure is 50% or 10% if one considers the validation by ligand-observed NMR spectroscopy or X-ray crystallography, respectively. Compounds 1 and 3 show favorable ligand efficiency in two different in vitro binding assays. The structure of the CBP bromodomain in the complex with the brominated pyrrole 1 suggests fragment growing by Suzuki coupling.

PubMed: 28410781
DOI: 10.1016/j.bmcl.2017.04.001

Experimental method

X-RAY DIFFRACTION (1.65 Å)