<br>PROTAC 复杂结构的高精度预测,Journal of the American Chemical Society

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PROTAC 复杂结构的高精度预测
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-03-24 , DOI: 10.1021/jacs.2c09387
Mikhail Ignatov _{1,

2} , Akhil Jindal _{1,

2} , Sergei Kotelnikov _{1,

2} , Dmitri Beglov _{3,

4} , Ganna Posternak _{5,

6} , Xiaojing Tang ₅ , Pierre Maisonneuve ₅ , Gennady Poda _{7,

8} , Robert A Batey ₆ , Frank Sicheri _{5,

9,

10} , Adrian Whitty ₁₁ , Peter J Tonge ₁₂ , Sandor Vajda _{3,

11} , Dima Kozakov _{1,

2}

Affiliation

Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794, United States.
Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States.
Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, United States.
Acpharis Inc., Holliston, Massachusetts 01746, United States.
Center for Molecular, Cell and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario L4K-M9W, Canada.
Department of Chemistry, University of Toronto, Toronto, Ontario L4K-M9W, Canada.
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario L4K-M9W, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario L4K-M9W, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario L4K-M9W, Canada.
Department of Biochemistry, University of Toronto, Toronto, Ontario L4K-M9W, Canada.
Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States.
Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.

蛋白水解靶向嵌合体 (PROTAC) 的设计需要将 E3 连接酶置于靶蛋白附近，通过其泛素化和降解来调节后者的浓度。在这里，我们提出了一种生成 E3 连接酶-PROTAC-靶蛋白三元复合物高精度结构模型的方法。该方法依赖于两项计算创新：在高效的蛋白质-蛋白质对接程序中添加“沉默”卷积项，以消除不具有可接受的接头构象的蛋白质位姿；以及使用相同 E3 连接酶并靶向多个 PROTAC 的聚类模型。相同的蛋白质。结果表明，最大的共有簇总是具有较高的预测准确性，并且模型集合可用于预测与 PROTAC 降解活性相关的三元复合物的解离速率和协同性。该方法通过对已知 PROTAC 结构的应用以及针对 BRAF 突变体 V600E 的 PROTAC 盲测来证明。结果证实，PROTAC 通过稳定 E3 连接酶和靶蛋白之间有利的相互作用来发挥作用，但不一定利用最有利的几何结构来实现蛋白质之间的相互作用。

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更新日期：2023-03-24

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