Stereochemistry in the disorder–order continuum of protein interactions

化学 氨基酸 手性(物理) 内在无序蛋白质 立体化学 折叠(DSP实现) 蛋白质折叠 配体(生物化学) 蛋白质结构 生物化学 物理 手征对称性 受体 工程类 量子力学 Nambu–Jona Lasinio模型 电气工程 夸克
作者
Estella A. Newcombe,Amanda D. Due,Andrea Sottini,Steffie Elkjær,Frederik Friis Theisen,Catarina B. Fernandes,Lasse Staby,Elise Delaforge,Christian R. O. Bartling,Inna Brakti,Katrine Bugge,Benjamin Schuler,Karen Skriver,Johan G. Olsen,Birthe B. Kragelund
出处
期刊:Nature [Nature Portfolio]
标识
DOI:10.1038/s41586-024-08271-6
摘要

Intrinsically disordered proteins can bind via the formation of highly disordered protein complexes without the formation of three-dimensional structure1. Most naturally occurring proteins are levorotatory (l)—that is, made up only of l-amino acids—imprinting molecular structure and communication with stereochemistry2. By contrast, their mirror-image dextrorotatory (d)-amino acids are rare in nature. Whether disordered protein complexes are truly independent of chiral constraints is not clear. Here, to investigate the chiral constraints of disordered protein–protein interactions, we chose as representative examples a set of five interacting protein pairs covering the disorder–order continuum. By observing the natural ligands and their stereochemical mirror images in free and bound states, we found that chirality was inconsequential in a fully disordered complex. However, if the interaction relied on the ligand undergoing extensive coupled folding and binding, correct stereochemistry was essential. Between these extremes, binding could be observed for the d-ligand with a strength that correlated with disorder in the final complex. These findings have important implications for our understanding of the molecular processes that lead to complex formation, the use of d-peptides in drug discovery and the chemistry of protein evolution of the first living entities on Earth. Studies on protein–protein interactions using proteins containing d- or l-amino acids show that stereoselectivity of binding varies with the degree of disorder within the complex.
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