Target-conditioned diffusion generates potent TNFR superfamily antagonists and agonists

IF 44.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Science Pub Date : 2024-12-05 DOI:10.1126/science.adp1779
Matthias Glögl, Aditya Krishnakumar, Robert J. Ragotte, Inna Goreshnik, Brian Coventry, Asim K. Bera, Alex Kang, Emily Joyce, Green Ahn, Buwei Huang, Wei Yang, Wei Chen, Mariana Garcia Sanchez, Brian Koepnick, David Baker
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引用次数: 0

Abstract

Despite progress in designing protein-binding proteins, the shape matching of designs to targets is lower than in many native protein complexes, and design efforts have failed for the tumor necrosis factor receptor 1 (TNFR1) and other protein targets with relatively flat and polar surfaces. We hypothesized that free diffusion from random noise could generate shape-matched binders for challenging targets and tested this approach on TNFR1. We obtain designs with low picomolar affinity whose specificity can be completely switched to other family members using partial diffusion. Designs function as antagonists or as superagonists when presented at higher valency for OX40 and 4-1BB. The ability to design high-affinity and high-specificity antagonists and agonists for pharmacologically important targets in silico presages a coming era in protein design in which binders are made by computation rather than immunization or random screening approaches.
靶条件扩散产生有效的TNFR超家族拮抗剂和激动剂
尽管在设计蛋白质结合蛋白方面取得了进展,但设计与靶标的形状匹配度低于许多天然蛋白质复合物,并且针对肿瘤坏死因子受体1 (TNFR1)和其他具有相对平坦和极性表面的蛋白质靶标的设计努力失败了。我们假设随机噪声的自由扩散可以为具有挑战性的目标产生形状匹配的结合物,并在TNFR1上测试了这种方法。我们获得了具有低皮摩尔亲和力的设计,其特异性可以通过部分扩散完全切换到其他家族成员。设计的OX40和4-1BB在更高的效价下起拮抗剂或超激动剂的作用。为药理学上重要的靶点设计高亲和力和高特异性拮抗剂和激动剂的能力预示着蛋白质设计的一个即将到来的时代,在这个时代,结合剂是通过计算而不是免疫或随机筛选方法来制造的。
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来源期刊
Science
Science 综合性期刊-综合性期刊
CiteScore
61.10
自引率
0.90%
发文量
0
审稿时长
2.1 months
期刊介绍: Science is a leading outlet for scientific news, commentary, and cutting-edge research. Through its print and online incarnations, Science reaches an estimated worldwide readership of more than one million. Science’s authorship is global too, and its articles consistently rank among the world's most cited research. Science serves as a forum for discussion of important issues related to the advancement of science by publishing material on which a consensus has been reached as well as including the presentation of minority or conflicting points of view. Accordingly, all articles published in Science—including editorials, news and comment, and book reviews—are signed and reflect the individual views of the authors and not official points of view adopted by AAAS or the institutions with which the authors are affiliated. Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit recognition by the wider scientific community and general public provided by publication in Science, beyond that provided by specialty journals. Science welcomes submissions from all fields of science and from any source. The editors are committed to the prompt evaluation and publication of submitted papers while upholding high standards that support reproducibility of published research. Science is published weekly; selected papers are published online ahead of print.
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