Grant: Single-PI NIH R01 grant of $1.14 million over four years. This is the first single-PI NIH R01 grant at Mines
biomedical career.Title: Allosteric control of collagen fibril degradation by matrix metalloprotease-1Abstract: Fibrils are the extracellular matrix (ECM) components that provide a scaffold for resident cells to maintain tissue integrity. Collagen fibril degradation by matrix metalloproteases (MMPs) is involved in the majority of the top ten causes of death and plays an essential role in normal and pathological tissue remodeling. Despite such overwhelming significance in human health, the mechanism of fibril degradation (as opposed to well-studied monomers) by MMPs is lacking, which limits the full potential of MMP ligands for therapeutics. Additionally, targeting MMPs for improving human health is challenging because MMPs interact with and degrade many proteins in the human body. Due to such diverse functions, any drug used for inhibiting MMPs results in adverse side effects. If we can identify allosteric ligands that bind at distant sites and change the activity, we may alter MMP1 activity on collagen fibrils with higher specificity and fewer side effects. This grant will enable molecular understanding of collagen fibril degradation by MMPs using a multidisciplinary approach and reveal general principles of protein function at the fundamental level.Broader impact for human health: Most drugs target proteins in our body to make us feel better. All drugs have some side effects because they also affect unintended functions. We still do not know how to control protein for a specific function. Over the years, we have developed methods for precision control that this grant will support testing experimentally. If successful, we will be able to develop drugs with a fewer side effects. Importantly, we will be able to target MMPs for drug discovery in many human diseases, an elusive goal for several decades.