Department of Biophysics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093, Warsaw, Poland.
Sci Rep. 2021 Jun 28;11(1):13376. doi: 10.1038/s41598-021-92881-x.
MMP-9 plays a number of important physiological functions but is also responsible for many pathological processes, including cancer invasion, metastasis, and angiogenesis. It is, therefore, crucial to understand its enzymatic activity, including activation and inhibition mechanisms. This enzyme may also be partially involved in the "cytokine storm" that is characteristic of COVID-19 disease (SARS-CoV-2), as well as in the molecular mechanisms responsible for lung fibrosis. Due to the variety of processing pathways involving MMP-9 in biological systems and its uniqueness due to the O-glycosylated domain (OGD) and fibronectin-like (FBN) domain, specific interactions with its natural TIMP-1 inhibitor should be carefully studied, because they differ significantly from other homologous systems. In particular, earlier experimental studies have indicated that the newly characterised circular form of a proMMP-9 homotrimer exhibits stronger binding properties to TIMP-1 compared to its monomeric form. However, molecular structures of the complexes and the binding mechanisms remain unknown. The purpose of this study is to fill in the gaps in knowledge. Molecular modelling methods are applied to build the inhibitory and non-inhibitory MMP-9-TIMP-1 complexes, which allows for a detailed description of these structures and should allow for a better understanding of the regulatory processes in which MMP-9 is involved.
基质金属蛋白酶 9（MMP-9）在许多生理过程中发挥着重要作用，但同时也与许多病理过程有关，包括癌症侵袭、转移和血管生成。因此，了解其酶活性，包括激活和抑制机制，是至关重要的。这种酶可能也部分参与了 COVID-19 疾病（SARS-CoV-2）的“细胞因子风暴”，以及导致肺纤维化的分子机制。由于 MMP-9 在生物系统中涉及多种加工途径，并且由于其 O-糖基化结构域（OGD）和纤维连接蛋白样结构域（FBN）的独特性，与天然 TIMP-1 抑制剂的特异性相互作用应该仔细研究，因为它们与其他同源系统有很大的不同。特别是，早期的实验研究表明，与单体形式相比，新表征的 proMMP-9 三聚体的环状形式对 TIMP-1 表现出更强的结合特性。然而，复合物的分子结构和结合机制仍然未知。本研究的目的是填补知识空白。应用分子建模方法构建抑制性和非抑制性 MMP-9-TIMP-1 复合物，这使得对这些结构进行详细描述成为可能，并应该有助于更好地理解 MMP-9 参与的调节过程。
