小柯机器人

西班牙巴塞罗那科学技术学院Ben Lehner研究团队揭示抑制KRAS的能量和异构图谱。这一研究成果于2023年12月18日在线发表在国际学术期刊《自然》上。

研究人员通过绘制KRAS中抑制性异构交流的多个全局图谱来弥补这一不足。研究人员量化了超过26000个突变对KRAS折叠及其与六个相互作用伙伴结合的影响。双突变体中的基因相互作用使研究人员能够进行大规模的生物物理测量，推断出大于22000个因果自由能变化。这些能谱量化了突变如何调整信号蛋白的结合特异性，并绘制了一个重要治疗靶点的抑制性异构位点图。

异构传播在KRAS的中心β片上特别有效，多个表面口袋经基因验证具有异构活性，包括蛋白质C端叶的一个远端口袋。异构突变通常会抑制与所有受测效应物的结合，但也会改变结合的特异性，从而揭示出调整通路激活的调节、演化和治疗潜力。利用这个方法可以快速、全面地确定许多蛋白质中的异构作用靶点。

据悉，目前，数以千计的蛋白质已通过基因验证，成为数百种人类疾病的治疗靶点。然而，真正成功靶向的蛋白质却寥寥无几，许多蛋白质被认为是“不可药用”的。对于通过蛋白质-蛋白质相互作用发挥作用的蛋白质来说，情况尤其如此：直接抑制结合界面非常困难，需要确定异构位点。然而，大多数蛋白质都没有已知的异构位点，也不存在针对任何蛋白质的全面异构图谱。

附：英文原文

Title: The energetic and allosteric landscape for KRAS inhibition

Author: Weng, Chenchun, Faure, Andre J., Escobedo, Albert, Lehner, Ben

Issue&Volume: 2023-12-18

Abstract: Thousands of proteins have now been genetically-validated as therapeutic targets in hundreds of human diseases1. However, very few have actually been successfully targeted and many are considered ‘undruggable’. This is particularly true for proteins that function via protein-protein interactions: direct inhibition of binding interfaces is difficult, requiring the identification of allosteric sites. However, most proteins have no known allosteric sites and a comprehensive allosteric map does not exist for any protein. Here we address this shortcoming by charting multiple global atlases of inhibitory allosteric communication in KRAS. We quantified the impact of >26,000 mutations on the folding of KRAS and its binding to six interaction partners. Genetic interactions in double mutants allowed us to perform biophysical measurements at scale, inferring >22,000 causal free energy changes. These energy landscapes quantify how mutations tune the binding specificity of a signalling protein and map the inhibitory allosteric sites for an important therapeutic target. Allosteric propagation is particularly effective across the central beta sheet of KRAS and multiple surface pockets are genetically-validated as allosterically active, including a distal pocket in the C-terminal lobe of the protein. Allosteric mutations typically inhibit binding to all tested effectors but they can also change the binding specificity, revealing the regulatory, evolutionary and therapeutic potential to tune pathway activation. Using the approach described here it should be possible to rapidly and comprehensively identify allosteric target sites in many proteins.

DOI: 10.1038/s41586-023-06954-0

Source: https://www.nature.com/articles/s41586-023-06954-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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