6U8H

BRD2-BD1 in complex with the cyclic peptide 3.2_2

Summary for 6U8H

• Entry DOI: 10.2210/pdb6u8h/pdb
• Descriptor: Bromodomain-containing protein 2, cyclic peptide 3.2_2, IODIDE ION, ... (7 entities in total)
• Functional Keywords: bet, bromodomain, macrocyclic peptide, brd2, inhibitor, rapid, transcription-inhibitor complex, transcription, transcription/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 19150.84

Authors

Patel, K.,Walshe, J.L.,Walport, L.J.,Mackay, J.P. (deposition date: 2019-09-05, release date: 2020-08-19, Last modification date: 2023-11-15)

Primary citation

Patel, K.,Walport, L.J.,Walshe, J.L.,Solomon, P.D.,Low, J.K.K.,Tran, D.H.,Mouradian, K.S.,Silva, A.P.G.,Wilkinson-White, L.,Norman, A.,Franck, C.,Matthews, J.M.,Guss, J.M.,Payne, R.J.,Passioura, T.,Suga, H.,Mackay, J.P.
Cyclic peptides can engage a single binding pocket through highly divergent modes.
Proc.Natl.Acad.Sci.USA, 117:26728-26738, 2020

PubMed Abstract: Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 10-fold. Crystal structures of 13 peptide-bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and β-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.

PubMed: 33046654
DOI: 10.1073/pnas.2003086117

Experimental method

X-RAY DIFFRACTION (2.07 Å)