An Effective Strategy for Stabilizing Minimal Coiled Coil Mimetics.
An Effective Strategy for Stabilizing Minimal Coiled Coil Mimetics.
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DOI：
10.1021/jacs.5b05525
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发表时间：
2015-09-16
影响因子：
15
通讯作者：
Arora PS
中科院分区：
文献类型：
--
作者：
Wuo MG;Mahon AB;Arora PS
卷曲螺旋是蛋白质中的主要基序，并且协调对生物过程重要的各种复合物的多聚化。卷曲螺旋介导的相互作用的抑制具有显著的生物医学潜力。然而，提供具有限定的卷曲螺旋构象的短肽的一般方法仍然难以捉摸。我们评估了几种策略，以稳定最小的螺旋束，二聚体基序作为最初的焦点。通过用共价键取代螺旋间的离子键，在合成序列中实现了稳定的二聚体支架。将这种策略应用于更具挑战性的天然蛋白质-蛋白质相互作用（PPI）表明，需要额外的约束，即在内部a/d '位置沿着与e/e'位置的连接体的二硫键，以增强构象稳定性。我们预期本文所述的卷曲螺旋稳定方法产生新类别的PPI调节剂。
Coiled coils are a major motif in proteins and orchestrate multimerization of various complexes important for biological processes. Inhibition of coiled coil-mediated interactions has significant biomedical potential. However, general approaches that afford short peptides with defined coiled coil conformation remain elusive. We evaluated several strategies to stabilize minimal helical bundles, with the dimer motif as the initial focus. A stable dimeric scaffold was realized in a synthetic sequence by replacing an interhelical ionic bond with a covalent bond. Application of this strategy to a more challenging native protein–protein interaction (PPI) suggested that an additional constraint, a disulfide bond at the internal a/d′ position along with a linker at the e/e′ position, is required for enhanced conformational stability. We anticipate the coiled coil stabilization methodology described herein to yield new classes of modulators for PPIs.