Structure-Energy study of the interactions between matrix metalloproteinase 1 and tissue inhibitor of metalloproteinase

Matrix metalloproteinases MMPs are one of the major families of proteinases that play
key roles in maintaining an appropriately assembled extracellular matrix ECM. MMPs are
essential to many biological processes, such as wound healing, embryo implantation, bone
remodeling, and organogenesis. Their biological antagonists, the tissue inhibitors of
metalloproteinases TIMPs, regulate the enzymatic activities of MMPs. Uncontrolled ECM
degradation occurs when the delicate balance between TIMPs and MMPs is disrupted, resulting
in many diseases such as rheumatoid and osteoarthritis, cancer cell metastasis, and heart disease.
There are currently no effective treatments for osteoarthritis OA except for joint replacement
surgery. Therefore, gaining the knowledge about the structures and molecular mechanisms of
these key enzymes in order to uncover new ways to specifically inhibit these proteinases are an
opportunity for the development of therapeutics and treatments to prevent the joint destruction
seen in OA.
Our goal is to understand the biophysical interaction of catalytic domain of MMP-1 with NTIMP-
3 using isothermal calorimetry ITC. The ITC determines if binding between the proteins is
entropy or enthalpy driven and heat capacity will indicate the hydrophobic or hydrophilic
contributions of the interaction. The information from the ITC results in combination with the
known structures of N-TIMP-3/cd_MMP-1 will provide a more complete picture of the
interaction. This is in particular of relevance with respect clinical application by engineering
TIMPs for targeted inhibition of particular MMPs to treat diseases such as: cancer and arthritis.