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人类神经平素-1 b1片段的新晶体形式,具有六种静电突变,复合KDKPPR类联体

Ibrahima Goudiaby^1,2, Thérèse E Malliavin³, Eva Mocchetti¹

¹Université de Lorraine, CNRS, CRM2, F-54000 Nancy, France.

Molecules (Basel, Switzerland)

|July 29, 2023

概括

突变神经皮林1 (NRP1) 蛋白允许研究人员可视化其VEGF结合部位. 这种结构性洞察力有助于开发使用像KDKPPR.这样的酸来向质母细胞瘤治疗.

科学领域:

结构生物学是结构生物学.
癌症研究癌症研究
生物化学生物化学

背景情况:

神经皮林1 (NRP1) 是一种参与癌症发展和进展的共同受体.
在NRP1片段b1 (NRP1-b1) 中的VEGF结合口袋是关键的治疗点,特别是在质母细胞瘤中.
原生NRP1-b1晶体包装阻塞了VEGF结合部位,阻碍了连接体相互作用.

研究的目的:

为了克服结晶引起的NRP1-b1 VEGF结合部位的阻塞.
为了确定与KDKPPR结合的突变NRP1-b1的结构.
分析与NRP1.1结合的原子相互作用和动态.

主要方法:

在NRP1-b1表面的六个带电氨基酸的位点定向突变发生.
进行X射线晶体学以确定突变的NRP1-b1/KDKPPR复合物的结构.
使用多极电子密度模型和分子动力学模拟分析原子相互作用.

主要成果:

突变的NRP1-b1形成了一个新的晶体形式,暴露了VEGF结合裂.
KDKPPR的C端部分占据了暴露的结合部位.
分析揭示了Asp320和Glu348在静电联体转向中的作用;模拟显示了循环的移动性.

结论:

蛋白质工程成功实现了对NRP1-b1 VEGF结合部位的可视化.
结构和动态见解为设计向质母细胞瘤治疗提供了基础.
在药物开发中,了解原子水平上的联结体-蛋白相互作用至关重要.

关键词:

赫什菲尔德界面的接口神经皮林 1 1 神经皮林在X射线晶体学.静电的影响静电影响连接器连接器连接器分子动力学模拟模拟变种变种变种变种变种

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Conserved Binding Sites

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...