捷克科学院有机化学和生物化学研究所Lubomir Rulisek研究团队发现，配体分子的张力及其构象的复杂性是决定环二核苷酸与STING蛋白结合的主要因素。这一研究成果发表在2021年2月22日出版的国际学术期刊《德国应用化学》上。

在该研究中，课题组人员将结构生物学、等温量热法（ITC）和计算机模拟结合在一起，以阐明STING与六种环二核苷酸（CDN）结合的主要因素，这六种CDN其中包括三对天然（核糖）核苷酸和2'-氟代核糖的3,3'-CDN。{STING：CDN}配合物的X射线结构分析没有为所研究配体的亲和力不同提供任何解释。ITC显示，这组类似配体的熵/焓补偿高达25 kcal·mol^-1。借助于计算机模拟，研究人员认为氟代核糖配体的较高亲和力可以通过结合时熵的损失较小以及张力（自由）能较小来解释。

据了解，STING（干扰素基因刺激蛋白）是先天免疫的关键调节器，近年来被认为是一个很有前景的药物靶标。STING被环二核苷酸(CDNs)激活，最终导致I型干扰素和其他细胞因子的表达。迄今为止，人们对决定各种CDN类似物亲和力的因素知之甚少。

附：英文原文

Title: Ligand Strain and Its Conformational Complexity Is a Major Factor Determining Binding of Cyclic Dinucleotides to STING Protein

Author: Lubomí, Miroslav Smola, Ondrej Gutten, Milan Dejmek, Milan Ko, Thomas Evangelidis, Zahra Aliakbar Tehrani, Barbora Novotn, Radim Nencka, Gabriel Birku&#x, Evzen Boura

Issue&Volume: 2021-02-22

Abstract: STING (stimulator of interferon genes) is a key regulator of innate immunity that has recently been recognized as a promising drug target. STING is activated by cyclic dinucleotides (CDNs) which eventually leads to expression of type I interferons and other cytokines. Factors underlying the affinity of various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) and computational modeling to elucidate factors contributing to binding of six CDNs – three pairs of natural (ribo) and fluorinated (2'‐fluororibo) 3,3’‐CDN’s. X‐ray structural analyses of six {STING:CDN} complexes ‐ did not offer any explanation for different affinities of the studied ligands. ITC showed entropy/enthalpy compensation up to 25 kcal.mol  ‐1  for this set of similar ligands. The higher affinities of fluorinated analogues are explained with help of computational methods by smaller loss of entropy upon binding and by smaller strain (free) energy.

DOI: 10.1002/anie.202016805

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202016805