Stereochemistry in the disorder-order continuum of protein interactions

• 成果类型: Article
• 署名作者: Newcombe, Estella A.; Due, Amanda D.; Sottini, Andrea; Elkjaer, Steffie; Theisen, Frederik Friis; Fernandes, Catarina B.; Staby, Lasse; Delaforge, Elise; Bartling, Christian R. O.; Brakti, Inna; Bugge, Katrine; Schuler, Benjamin; Skriver, Karen; Olsen, Johan G.; Kragelund, Birthe B.
• 署名单位: University of Copenhagen; University of Copenhagen; University of Copenhagen; University of Zurich; University of Zurich; University of Copenhagen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4887
• DOI: 10.1038/s41586-024-08271-6
• 发表日期: 2024-12-19
• 关键词: amino-acids; peptides; binding; RECOGNITION; prediction; exchange; regions; jnk

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.