丹麦哥本哈根大学Kragelund, Birthe B.团队报道了蛋白质相互作用无序-有序连续体中的立体化学。相关研究成果发表在2024年11月27日出版的国际学术期刊《自然》。

内在无序的蛋白质可以通过形成高度无序的蛋白质复合物结合，而不会形成三维结构。大多数天然存在的蛋白质都是左旋的（L），即仅由L-氨基酸组成，这决定了分子结构和与立体化学的联系。相比之下，它们的镜像右旋（D）氨基酸在自然界中很少见。无序蛋白质复合物是否真正独立于手性约束尚不清楚。

该文中，为了研究无序蛋白质相互作用的手性约束，研究人员选择了一组覆盖无序-有序连续体的五对相互作用蛋白质对作为代表性例子。通过观察自由态和结合态的天然配体及其立体化学镜像，研究人员发现手性在完全无序的复合物中无关紧要。

然而，如果相互作用依赖于配体进行广泛的偶联折叠和结合，正确的立体化学至关重要。在这些极端之间，可以观察到D-配体的结合强度与最终复合物中的紊乱有关。这些发现对人们理解导致复杂结构形成的分子过程、D-肽在药物发现中的应用以及地球上第一批生物的蛋白质进化化学具有重要意义。

附：英文原文

Title: Stereochemistry in the disorder–order continuum of protein interactions

Author: Newcombe, Estella A., Due, Amanda D., Sottini, Andrea, Elkjr, 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.

Issue&Volume: 2024-11-27

Abstract: 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.

DOI: 10.1038/s41586-024-08271-6

Source: https://www.nature.com/articles/s41586-024-08271-6