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Framework for substrate-specific allosteric control of matrix metalloprotease-1 activity, A
Harms, Chase
Harms, Chase
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2024
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Abstract
Matrix Metalloproteases (MMPs), a 23-member family of human enzymes, act to degrade or interact with many biomolecules in the human body and have a direct or indirect role in many human disease processes. A mechanistic understanding of their diverse functions is necessary for targeting MMPs for potential therapeutics in human diseases. Unfortunately, why and how MMPs perform such a diverse range of functions in the human body is not well understood. As a result, any drug used to target MMP function may inhibit activity on intended targets, but also inhibit activity in other bodily functions. This has led to adverse side effects and failures in clinical trials. Consequently, there is only one FDA approved drug (tetracycline) to inhibit MMP activity. Controlling one MMP function without affecting others is critical to addressing the complications of diverse activity. This thesis develops a framework to modulate specific functions of MMPs, focusing on MMP1 which is most known for its ability to degrade triple-helical collagen
Since MMPs have largely similar catalytic domains (where enzymatic actions take place), it has been argued that the diversity of MMP functions is due to communications from distant parts of the enzyme (allosteric communications). Our central hypothesis is that these allosteric communications depend on the biomolecules (substrates) that MMPs interact with. Furthermore, we have found that MMP’s interactions with different substrates produce unique signatures or ‘fingerprints’ in their dynamics. These substrate-specific fingerprints provide the necessary information to screen drugs for experimental validation, which enables us to develop substrate-specific allosteric control of MMP activity.
Our lab has purified active and inactive forms of MMP1 and observed their interdomain dynamics. From these motions, we have developed a statistical model for MMP1’s behavior as a two-state Poisson process, and successfully run molecular dynamics simulations that match our experimental data. From these simulations we have identified the substrate-specific dynamical fingerprints for free MMP1, as well as MMP1 bound to collagen, fibrin, alpha-synuclein, and amyloid-beta. We have used these fingerprints to screen drugs against MMP1 and have shown the importance of biological substrate in drug binding.
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