8CV6

Peptide 4.2B in complex with BRD4.2

Summary for 8CV6

• Entry DOI: 10.2210/pdb8cv6/pdb
• Descriptor: BRD4 protein, Peptide 4.2E, ACETYL GROUP, ... (5 entities in total)
• Functional Keywords: cyclic peptide inhibitor bromodomain, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 16351.91

Authors

Franck, C.,Mackay, J.P. (deposition date: 2022-05-18, release date: 2023-05-24, Last modification date: 2023-12-06)

Primary citation

Franck, C.,Patel, K.,Walport, L.J.,Christie, M.,Norman, A.,Passioura, T.,Suga, H.,Payne, R.J.,Mackay, J.P.
Discovery and characterization of cyclic peptides selective for the C-terminal bromodomains of BET family proteins.
Structure, 31:912-923.e4, 2023

PubMed Abstract: DNA-encoded cyclic peptide libraries can yield high-potency, high-specificity ligands against target proteins. We used such a library to seek ligands that could distinguish between paralogous bromodomains from the closely related bromodomain and extra-terminal domain family of epigenetic regulators. Several peptides isolated from a screen against the C-terminal bromodomain of BRD2, together with new peptides discovered in previous screens against the corresponding domain from BRD3 and BRD4, bound their targets with nanomolar and sub-nanomolar affinities. X-ray crystal structures of several of these bromodomain-peptide complexes reveal diverse structures and binding modes, which nevertheless display several conserved features. Some peptides demonstrate significant paralog-level specificity, although the physicochemical explanations for this specificity are often not clear. Our data demonstrate the power of cyclic peptides to discriminate between very similar proteins with high potency and hint that differences in conformational dynamics might modulate the affinity of these domains for particular ligands.

PubMed: 37269828
DOI: 10.1016/j.str.2023.05.009

Experimental method

X-RAY DIFFRACTION (1.7 Å)