Cracking LDL Cholesterol: A Game-Changing Discovery
After decades of research, scientists have captured a high-resolution image of LDL cholesterol, revealing how it interacts with its receptor on human cells. This breakthrough could transform our understanding of cholesterol metabolism, genetic disorders, and future cardiovascular treatments.
A Long-Awaited Look at LDL
More than 50 years ago, scientists discovered the LDL receptor—the protein that pulls cholesterol-carrying low-density lipoprotein (LDL) particles out of the bloodstream and into cells. It was a discovery that revolutionized medicine and won a Nobel Prize. But while the function of LDL was known, its full 3D structure remained elusive for decades.
That changed recently when two research teams, including one from the U.S. National Institutes of Health (NIH), published breakthrough findings in Nature. Using cutting-edge technologies, they revealed the detailed structure of apolipoprotein B100 (apo B100)—the main protein in LDL—and, for the first time, visualized how LDL binds with its receptor on the surface of human cells.
This achievement could open the door to new treatments for familial hypercholesterolemia (FH), heart disease, and other cholesterol-related disorders. While clinical applications are still years away, experts say this leap in structural biology is a crucial step forward.
Breaking the "Resolution Glass Ceiling"
LDL is a massive, complex particle, and apo B100—its structural backbone—is one of the largest proteins in the human body. These characteristics made it nearly impossible to image with traditional structural biology tools like x-ray crystallography. Previous attempts produced only low-resolution snapshots.
To overcome this, researchers combined cryoelectron microscopy (cryo-EM) with AlphaFold, an advanced AI protein structure prediction tool. The NIH team also used an innovative cryo-EM tool called legobodies to stabilize and orient the molecules for imaging. The result was a detailed 3D map of LDL bound to its receptor.
“We had a lot of people tell us this couldn’t be done,” said Dr. Joseph Marcotrigiano, lead researcher at NIH’s National Institute of Allergy and Infectious Diseases. Originally drawn to the field through hepatitis C research, Marcotrigiano teamed up with Dr. Alan Remaley, a cholesterol expert at the NIH’s National Heart, Lung, and Blood Institute. Their unlikely collaboration started with a cold email—and a surprise visit from a colleague who turned out to be a neighbor.
Rewriting Textbooks: LDL Receptors Work in Pairs
One of the study’s most surprising findings was the discovery that LDL receptors operate in pairs, not alone as previously believed. According to Dr. Thomas Dayspring, a clinical lipidologist familiar with the work, this paired structure is more efficient—like two sets of lobster claws that clasp LDL particles with greater strength and speed.
This insight doesn’t just rewrite textbooks; it could help explain why some individuals with genetic mutations in their LDL receptors are unable to clear cholesterol effectively from their blood, leading to dangerously high LDL levels.
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