Cyclic peptides can engage a single binding pocket through highly divergent modesMore about Open Access at the Crick
Authors listKarishma Patel Louise Walport James L Walshe Paul D Solomon Jason KK Low Daniel H Tran Kevork S Mouradian Ana PG Silva Lorna Wilkinson-White Alexander Norman Charlotte Franck Jacqueline M Matthews J Mitchell Guss Richard J Payne Toby Passioura Hiroaki Suga Joel P Mackay
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 106-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.
Issue number 43