Cyclic peptides can engage a single binding pocket through highly divergent modes
Autor: | Toby Passioura, Alex Norman, Louise J. Walport, Ana P. G. Silva, Jacqueline M. Matthews, Hiroaki Suga, Joel P. Mackay, Charlotte Franck, James L. Walshe, Kevork S Mouradian, Daniel H Tran, Richard J. Payne, Lorna Wilkinson-White, Paul D Solomon, Jason Low, K. Patel, J. Mitchell Guss |
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Rok vydání: | 2020 |
Předmět: |
STRUCTURAL BASIS
MECHANISM 0301 basic medicine MACROCYCLIC PEPTIDES INHIBITION Binding pocket Computational biology Peptides Cyclic Biochemistry 01 natural sciences 03 medical and health sciences Functional diversity Protein Domains GATA1 Peptide Library Drug Discovery Humans structural biology chemistry.chemical_classification Science & Technology Binding Sites Multidisciplinary POTENT 010405 organic chemistry Chemistry RECOGNITION Biological Sciences Affinities Cyclic peptide 0104 chemical sciences Bromodomain Multidisciplinary Sciences TARGET de novo cyclic peptides 030104 developmental biology Structural biology DISCOVERY Science & Technology - Other Topics BRD4 BET bromodomain inhibition BRD3 Protein Binding Transcription Factors |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
ISSN: | 1091-6490 0027-8424 |
Popis: | Significance Large DNA-encoded libraries of cyclic peptides are emerging as powerful sources of molecules to tackle challenging drug targets. The structural and functional diversity contained within these libraries is, however, little explored. Here we demonstrate that one such library contains members that use unexpectedly diverse mechanisms to recognize the same surface on the same target proteins with high affinity and specificity. This range of binding modes is much larger than observed in natural ligands of the same proteins, demonstrating the power and versatility of the technology. Our data also reveal opportunities for the development of more sophisticated approaches to achieving specificity when trying to selectively target one member of a family of closely related proteins. 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. |
Databáze: | OpenAIRE |
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