Page 21 - The Hormel Institute 2024 Annual Report

Biological membranes are fundamental components of cellular and organellar structures that play a central role in normal
cellular functioning. My lab studies the molecular machinery controlling both the maintenance and homeostasis of these membrane structures and the tightly regulated passage of metabolites and xenobiotics across them. These can be divided into two classes. The first contains the set of membrane transport proteins whose dysfunction can underlie severe human metabolic and neu- rological conditions. The second includes those proteins whose normal functioning can either disrupt therapeutic intervention and complicate drug delivery and clearance or contribute to tumor growth in different cancer types. We use
a combination of structural biology approaches (primarily cryoEM), biochemistry, cell biology, and antibody, and small molecule discovery to both understand the fundamental functioning of these membrane proteins and develop novel tools for research as well as development of diagnostic
Through our work we are helping expand the list of “druggable” protein targets for therapeutic intervention through uncovering previously unresolved molecular mechanisms for both well-known and under-studied proteins involved in human health and disease.
and therapeutic modalities. Over the last year the lab has actively contributed to advancement in both these departments with the major high- lights being as follows:
1We continue to make breakthroughs in our investigation of ATP binding Cassette transporters that belong to the A and D
subfamilies whose dysfunction, with a particular focus on development of highly specific con- formational antibody fragments (nanobodies) against them. These nanobodies open the door for novel and unique research directions and techniques to probe the molecular functioning of these proteins, they have the potential to
be developed into diagnostic and therapeutic probes for on cell detection and targeted drug delivery. We are currently focusing on the patent- ing of these sequences and their derivatives and exploring possibilities for their eventual licensing and commercialization.
2We have made major breakthroughs in the detailed structural investigation of human ABCB1, also known as MDR1 or p-glyco-
protein. This protein, which is listed on the FDA’s guidance document for all developmental drugs to be screened against, carries plays a central role in cellular detoxifications, chemotherapy resistance of cancer cells in cancer cells, and drug pharmacokinetics and bioavailability. We have provided the first-time structures of this transporter in multiple states of its transport cycle, providing fundamental insights into its function that will have a broad impact on.
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