Cyclic peptides can engage a single binding pocket through highly divergent modes.
Cyclic peptides can engage a single binding pocket through highly divergent modes.
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DOI：
10.1073/pnas.2003086117
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发表时间：
2020-10-27
影响因子：
11.1
通讯作者：
Mackay JP
中科院分区：
文献类型：
--
作者：
Patel K;Walport LJ;Walshe JL;Solomon PD;Low JKK;Tran DH;Mouradian KS;Silva APG;Wilkinson-White L;Norman A;Franck C;Matthews JM;Guss JM;Payne RJ;Passioura T;Suga H;Mackay JP
大型DNA编码的环肽文库正在成为解决具有挑战性的药物靶点的强大分子来源。然而，这些库中所包含的结构和功能多样性却很少被探索。在这里，我们证明了一个这样的库包含的成员，使用意想不到的不同机制，以高亲和力和特异性识别相同的目标蛋白的相同表面。这种结合模式的范围比在相同蛋白质的天然配体中观察到的要大得多，证明了该技术的能力和多功能性。我们的数据还揭示了开发更复杂的方法来实现特异性的机会，当试图选择性地靶向一个密切相关的蛋白质家族的一个成员时。环肽库筛选技术显示出巨大的前景，用于识别药物先导和化学探针的挑战性目标。然而，这种文库中编码的结构和功能多样性在很大程度上是不确定的。我们已经系统地分析了文库衍生的环肽的亲和力、选择性和结构特征，所述环肽被选择用于识别三个密切相关的靶标：乙酰赖氨酸结合溴结构域蛋白BRD 2、BRD-3和BRD-4。我们报告的亲和力低至100 pM和高达106倍的特异性。13个多肽-溴结构域复合物的晶体结构在结构和结合模式上都表现出显著的多样性，既有α-螺旋结构，也有β-折叠结构，还有二价结合模式。所述肽还可以表现出高度的结构预组织。我们的数据表明，这些库具有巨大的潜力，可以针对单一靶标提供多种结合模式，这支持了它们产生高效和选择性配体的能力。
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.
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DOI：
10.1126/science.aaz8455
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilan O;Rioja I;Knezevic K;Bell MJ;Yeung MM;Harker NR;Lam EYN;Chung CW;Bamborough P;Petretich M;Urh M;Atkinson SJ;Bassil AK;Roberts EJ;Vassiliadis D;Burr ML;Preston AGS;Wellaway C;Werner T;Gray JR;Michon AM;Gobbetti T;Kumar V;Soden PE;Haynes A;Vappiani J;Tough DF;Taylor S;Dawson SJ;Bantscheff M;Lindon M;Drewes G;Demont EH;Daniels DL;Grandi P;Prinjha RK;Dawson MA
通讯作者：
Dawson MA
影响因子：
15
作者：
Gerona-Navarro G;Yoel-Rodríguez;Mujtaba S;Frasca A;Patel J;Zeng L;Plotnikov AN;Osman R;Zhou MM
通讯作者：
Zhou MM
影响因子：
16.6
作者：
Kawamura A;Münzel M;Kojima T;Yapp C;Bhushan B;Goto Y;Tumber A;Katoh T;King ON;Passioura T;Walport LJ;Hatch SB;Madden S;Müller S;Brennan PE;Chowdhury R;Hopkinson RJ;Suga H;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
4
作者：
Goldbach, Leander;Vermeulen, Bram J. A.;Jongkees, Seino A. K.
通讯作者：
Jongkees, Seino A. K.
影响因子：
--
作者：
Pérez-Salvia M;Simó-Riudalbas L;Llinàs-Arias P;Roa L;Setien F;Soler M;de Moura MC;Bradner JE;Gonzalez-Suarez E;Moutinho C;Esteller M
通讯作者：
Esteller M