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电脑设计的矩阵金属蛋白-9 (MMP-9) 抗自动裂变的设计

Alessandro Bonadio¹, Solomon Oguche¹, Tali Lavy²

¹Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

The Biochemical journal

|July 4, 2023

概括

研究人员设计了一个稳定的矩阵金属蛋白酶-9催化域 (MMP-9Cat) 变体Des2,用于药物设计. 这种稳定的MMP-9Cat变体保持活力并抵抗自动裂变,克服了治疗开发中的局限性.

科学领域:

生物化学生物化学
酶学是一种酶学.
药物发现药物发现药物发现

背景情况:

矩阵金属蛋白酶-9 (MMP-9) 在细胞外矩阵重塑中至关重要,并与癌症和关节炎等疾病有关.
MMP-9 (MMP-9Cat) 的催化域不稳定,快速自裂,这阻碍了其在药物设计和生物物理研究中的使用.
对于MMP-9抑制剂的治疗应用需求很高,需要稳定的酶变体.

研究的目的:

设计和验证MMP-9催化域 (MMP-9Cat) 的一个活跃但耐自动裂变的变体.
克服MMP-9Cat固有的不稳定性,以提高药物发现和生物物理研究中的效用.

主要方法:

在MMP-9Cat上使用质谱测量确定了自动裂变点.
设计突变以最大限度地降低自身分裂潜力,同时保持酶的稳定性和活性.
通过实验构建和评估了四种经过计算设计的MMP-9Cat变体.

主要成果:

最好的变体Des2,有两个突变,表现出与野生型MMP-9Cat相比的活性.
德斯2表现出了显著的稳定性,在37°C的化7天后没有表现出自动裂变.
Des2的活性部位与野生型MMP-9Cat.相同.

结论:

稳定的MMP-9Cat变体 (Des2) 适用于针对MMP-9的药物设计和酶结晶.
稳定MMP-9Cat的策略可以应用于其他蛋白酶,增强其生物技术应用的稳定性.

关键词:

在MMP-9中,它是MMP-9的.自动切割自动切割自动降解的自动降解.酶工程是指酶工程的工程.矩阵金属蛋白质酶是什么蛋白质工程工程蛋白质工程

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