A Healthier Wisconsin

Solving Protein Structures to Uncover Molecular Mechanisms of Cancer

Equipping and staffing a state-of-the-art facility to solve the atomic-level structure of cancer-relevant proteins

Full Project Name:Solving Protein Structures to Uncover Molecular Mechanisms of CancerPrincipal Investigator:Gustavo Leone, PhD, Cancer Center and BiochemistryCo-Investigator:Wei Lui, PhD, Pharmacology and ToxicologyAward Amount:$5,500,000
Award Date
Project Duration:96 months

Project Description Narrative:

In 2022, over 36,000 Wisconsinites will be newly diagnosed with cancer, and 11,700 will die from it. The Medical College of Wisconsin Cancer Center is dedicated to developing, translating, and offering novel therapies to improve cancer survivorship and decrease cancer outcomes disparities throughout the state. Knowing a protein's 3D structure is a critical asset necessary to understand mechanisms underlying protein function because proteins' interactions with other proteins or with drugs are mediated by their shape along with electrical and chemical properties. Such mechanistic understanding can be applied to develop effective cancer therapeutics by designing drugs that bind proteins involved in cancer in a highly specific manner to inhibit or activate them.

Since 2010, cryo-electron microscopy (cryo-EM) has emerged as a powerful new means to map proteins' shapes. By establishing a cryo-EM capability and expanding collaborations with multidisciplinary teams of scientists, the researchers propose to unravel the underlying mechanisms driving cancer initiation, progression, and metastasis, paving the way for future studies to evaluate and optimize drugs that target these mechanisms and providing significant benefits to cancer patients in Wisconsin.

Through this partnership with AHW, the researchers will establish a pipeline using cryo-EM to solve the structures of important membrane-bound proteins, such as G protein-coupled receptors (GPCRs) and other cancer-relevant protein targets. By doing so, they will provide the data required for structure-based drug design, paving the way for novel therapeutics that will have superior efficacy and fewer negative side effects than currently available cancer drugs. These more effective drugs will be better tolerated by patients, markedly reduce or eliminate their tumors, increase their disease-free and overall survival, and improve the quality of life after cancer.

Project Updates:

  • Launched the protein production facility to a fully operational state to provide users from all areas of research access to the high-quality protein necessary to advance their research
  • Consulted with 17 researchers and working on protein production projects for 11 investigators, enabling researchers to advance their studies in new and faster ways, bringing tangible health care benefits to Wisconsin residents
  • Over 20 projects completed or in progress to solve the structures of cancer-relevant target proteins with the completed projects contributing to four publications and four additional manuscripts submitted for review
  • Preparing the building and environment for the Glacios microscope for the Cryo-EM facility

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