Department of Chemistry, Michigan Technological University, Houghton, MI, 49931, USA.
Department of Chemistry and Biochemistry and I-HEALTH, Florida Atlantic University, Jupiter, FL, 33458, USA.
J Biol Inorg Chem. 2021 Aug;26(5):583-597. doi: 10.1007/s00775-021-01876-6. Epub 2021 Jul 6.
Matrix metalloproteinases (MMPs) are Zn(II) dependent endopeptidases involved in the degradation of collagen. Unbalanced collagen breakdown results in numerous pathological conditions, including cardiovascular and neurodegenerative diseases and tumor growth and invasion. Matrix metalloproteinase-1 (MMP-1) is a member of the MMPs family. The enzyme contains catalytic and structural Zn(II) ions. Despite many studies on the enzyme, there is little known about the synergy between the two Zn(II) metal ions and the enzyme and substrate dynamics in MMP-1 structure-function relationships. We performed a computational study of the MMP-1•triple-helical peptide (THP) enzyme•substrate complex to provide this missing insight. Our results revealed Zn(II) ions' importance in modulating the long-range correlated motions in the MMP-1•THP complex. Overall, our results reveal the importance of the catalytic Zn(II) and the role of the structural Zn(II) ion in preserving the integrity of the enzyme active site and the overall enzyme-substrate complex synergy with the dynamics of the enzyme and the substrate. Notably, both Zn(II) sites participate in diverse networks of long-range correlated motions that involve the CAT and HPX domains and the THP substrate, thus exercising a complex role in the stability and functionality of the MMP-1•THP complex. Both the Zn(II) ions have a distinct impact on the structural stability and dynamics of the MMP-1•THP complex. The study shifts the paradigm from the "local role" of the Zn(II) ions with knowledge about their essential role in the long-range dynamics and stability of the overall enzyme•substrate (ES) complex.
基质金属蛋白酶（MMPs）是依赖锌（II）的内肽酶，参与胶原的降解。胶原的不平衡分解导致许多病理状况，包括心血管和神经退行性疾病以及肿瘤的生长和侵袭。基质金属蛋白酶-1（MMP-1）是 MMPs 家族的一员。该酶包含催化和结构锌（II）离子。尽管对该酶进行了许多研究，但对于两个锌（II）金属离子与酶以及 MMP-1 结构-功能关系中酶和底物动力学之间的协同作用知之甚少。我们对 MMP-1•三螺旋肽（THP）酶•底物复合物进行了计算研究，以提供这一缺失的见解。我们的结果表明，锌（II）离子在调节 MMP-1•THP 复合物中的长程相关运动方面具有重要作用。总体而言，我们的结果揭示了催化锌（II）离子的重要性以及结构锌（II）离子在保持酶活性位点完整性和整体酶-底物复合物协同作用与酶和底物动力学方面的作用。值得注意的是，两个锌（II）位点都参与了涉及 CAT 和 HPX 结构域以及 THP 底物的长程相关运动的多种网络，从而在 MMP-1•THP 复合物的稳定性和功能中发挥复杂作用。两个锌（II）离子都对 MMP-1•THP 复合物的结构稳定性和动力学有明显影响。该研究将范式从锌（II）离子的“局部作用”转变为它们在整体酶-底物（ES）复合物的长程动力学和稳定性中的重要作用。
