Cyclic peptides can engage a single binding pocket through highly divergent modes

Patel Karishma; Walport Louise J.; Walshe James L.Solomon Paul D.Low Jason K. K.Tran Daniel H.Mouradian Kevork S.Silva Ana P. G.Wilkinson-White LornaNorman AlexanderFranck CharlotteMatthews Jacqueline M.Guss J. MitchellPayne Richard J.Passioura TobySuga HiroakiMackay Joel P.

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Cyclic peptides can engage a single binding pocket through highly divergent modes

机译：Cyclic peptides can engage a single binding pocket through highly divergent modes

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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(6)-fold. Crystal structures of 13 peptide-bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both alpha-helical and beta-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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2020年第43期|26728-26738|共11页
作者
Patel Karishma; Walport Louise J.; Walshe James L.Solomon Paul D.Low Jason K. K.Tran Daniel H.Mouradian Kevork S.Silva Ana P. G.Wilkinson-White LornaNorman AlexanderFranck CharlotteMatthews Jacqueline M.Guss J. MitchellPayne Richard J.Passioura TobySuga HiroakiMackay Joel P.;
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作者单位

Sch Life & Environm Sci,Univ Sydney;

Prot Prot Interact Lab,Francis Crick Inst;

Sch Chem,Univ SydneySydney Analyt Core Res Facil,Univ SydneyGrad Sch Sci,Univ Tokyo;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
de novo cyclic peptides; BET bromodomain inhibition; structural biology; BRD3; BRD4; MACROCYCLIC PEPTIDES; STRUCTURAL BASIS; DISCOVERY; RECOGNITION; INHIBITION; MECHANISM; TARGET; POTENT; GATA1;

Cyclic peptides can engage a single binding pocket through highly divergent modes

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