5LUU

Structure of the first bromodomain of BRD4 with a pyrazolo[4,3-c]pyridin fragment

Summary for 5LUU

• Entry DOI: 10.2210/pdb5luu/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one, ... (4 entities in total)
• Functional Keywords: fragment, complex, bromodomain, structural genomics, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15478.83

Authors

Filippakopoulos, P.,Picaud, S.,Knapp, S.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Structural Genomics Consortium (SGC) (deposition date: 2016-09-11, release date: 2016-10-12, Last modification date: 2024-05-08)

Primary citation

Navratilova, I.,Aristotelous, T.,Picaud, S.,Chaikuad, A.,Knapp, S.,Filappakopoulos, P.,Hopkins, A.L.
Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.
ACS Med Chem Lett, 7:1213-1218, 2016

PubMed Abstract: The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains. High-resolution crystal structures of the complexes of key fragments binding to BRD4(1), CREBBP, and PCAF were determined to provide binding mode data to aid the development of potent and selective inhibitors of PCAF, CREBBP, and BRD4.

PubMed: 27994766
DOI: 10.1021/acsmedchemlett.6b00154

Experimental method

X-RAY DIFFRACTION (1.61 Å)