Breakthrough EMBO Journal study generates never-before-seen insights on a protein critical for chemotherapy
Appearing in The EMBO Journal, the breakthrough study reveals new information about a protein called ABCB1—including a never-before-seen structure in significant contrast to AI modeling predictions. The protein plays a key role in drug resistance, a major challenge in oncology, and the new insights from this study may hold the key for developing more effective pharmacological treatments for cancer, Alzheimer's disease, and more.
"Given its critical role in medicine and drug development, ABCB1 has been extensively studied, yet key details about its function have remained elusive. Our findings bridge longstanding gaps in understanding how this protein interacts with lipids and drugs, helping to reconcile decades of genetic and cellular studies," Alam said. "The structural data we present sets a new benchmark for ABCB1 research and will have widespread implications for the fields of pharmacology, structural biology, and drug discovery."
Using The Hormel Institute's cryogenic-sample electron microscopy (cryoEM) technology, the research team generated high-resolution, 3D snapshots of ABCB1 in four different states—including in its never-before-seen resting state, which, despite decades of research, has been unknown until now. The ability to take an even closer look at ABCB1 revealed a completely new shape with previously unrecognized features that challenge prior assumptions based on similar proteins.
"Surprisingly, our experimentally determined structure [of ABCB1 in its "apo" state] differs significantly from predictions made by AlphaFold, a leading AI-based protein modeling tool. This discovery highlights the current limitations of computational models and underscores the importance of direct experimental validation," Alam said. "Our findings also distinguish how certain drugs interact with ABCB1, either as transportable compounds or as inhibitors that lock the protein in specific states."
A family of proteins known as ATP-binding cassette (ABC) transporters move substances like sugars, lipids, amino acids, and pharmaceutical drugs across cell membranes and into or out of cells or cellular organelles. ABCB1—also known as Multidrug Resistance Protein 1 (MDR1) or P-glycoprotein—is an ABC transporter that operates like a pump, ejecting foreign substances from cells to detoxify them. Its action can determine the fate of drug therapy by affecting drug uptake and clearance from cells, which has led to the Food and Drug Administration (FDA) requiring all new drug candidates to be screened for ABCB1 interactions.
ABCB1 is most well-known for multidrug resistance (MDR). This is when cancer cells, in response to chemotherapy, can overproduce ABCB1, which actively pumps out the chemotherapeutic drugs and leads to therapy failure. MDR is considered a major hurdle when administering chemotherapy and can often become a contributing factor toward cancer deaths.
Post-Doctoral Associate Devanshu Kurre, PhD, Research Associate Phuoc X Dang, Post-Doctoral Associate Le Thi My Le, PhD, are also listed as authors of the paper. This research was supported in part by Eagles Cancer Postdoctoral Fellowships awarded to Dr. Kurre and Dr. Le.
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