Department of Chemistry and Biochemistry, University of California San Diego, San Diego, California, United States of America.
PLoS One. 2020 Dec 4;15(12):e0243321. doi: 10.1371/journal.pone.0243321. eCollection 2020.
Matrix metalloproteinase (MMP) is a class of metalloenzyme that cleaves peptide bonds in extracellular matrices. Their functions are important in both health and disease of animals. Here using quantum mechanics simulations of the MMP8 protein, the coordination chemistry of different metal cofactors is examined. Structural comparisons reveal that Jhan-Teller effects induced by Cu(II) coordination distorts the wild-type MMP8 active site corresponding to a significant reduction in activity observed in previous experiments. In addition, further analysis suggests that a histidine to glutamine mutation at residue number 197 can potentially allow the MMP8 protein to utilize Cu(II) in reactions. Simulations also demonstrates the requirement of a conformational change in the ligand before enzymatic cleavage. The insights provided here will assist future protein engineering efforts utilizing the MMP8 protein.
基质金属蛋白酶（MMP）是一类金属酶，可裂解细胞外基质中的肽键。它们的功能在动物的健康和疾病中都很重要。在这里，我们使用 MMP8 蛋白的量子力学模拟，研究了不同金属辅因子的配位化学。结构比较表明，Cu(II)配位引起的姜-泰勒效应扭曲了野生型 MMP8 活性位点，这与先前实验中观察到的活性显著降低相对应。此外，进一步的分析表明，残基 197 处的组氨酸到谷氨酰胺的突变可能使 MMP8 蛋白能够在反应中利用 Cu(II)。模拟还表明，在酶切之前，配体需要发生构象变化。这里提供的见解将有助于未来利用 MMP8 蛋白进行蛋白质工程的努力。
