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Great pictures of the molecules that supply the brain with omega-3 fatty acids can open the door to neurotherapeutic drug delivery to the brain.
“I managed to preserve the three-dimensional structure of the transporter. Protein It provides a gateway for omega-3 fatty acids to enter the brain. In this structure you can see how omega-3 binds to the transporter. This information could make it possible to develop drugs that mimic omega-3 fatty acids to hijack the system and enter the brain, ”said lead author, Simon’s Society Fellow, at the Mancia Institute in Bageros, Columbia University. Dr. Rosemary J. Kata said. University for Doctors and Surgeons.
This study was published online in the journal on June 16. Nature..
The main challenges in treating neurological disorders are the blood-brain barrier – a tightly packed layer of cells that covers the blood vessels of the brain and excites toxins, pathogens, and some nutrients from entering the brain. Unfortunately, this layer also blocks many drugs that are promising candidates for treating neuropathy.
Essential nutrients such as omega-3 require the support of special transport proteins that specifically recognize them and enable them to overcome this barrier. “Vans are like bouncers in clubs who only let invitations and molecules pass behind the scenes,” says Kata.
The van (or bouncer) that captures omega-3s is called MFSD2A and was the focus of Cater research. “To understand what MFSD2A looks like and how omega-3s are drawn across the blood-brain barrier, you need to develop a drug that can get this bouncer into a path of entry. Can provide us with the information we need. “
To visualize MFSD2A, Cater used a technique called single particle cryo-electron microscopy.
“The great thing about this technology is that you can see the shape of the van in a billionth of a meter,” said Dr. Filippomancia, Associate Professor of Physiology and Co-Head of the Study. Expert in Cell Biophysics, Columbia University Vagelos College of Physicians and Surgeons, and Structure and Function of Membrane Proteins. “This information is important to understand how transporters work at the molecular level.”
In cryo-EM analysis, protein molecules are suspended in a thin layer of ice under an electron microscope. Powerful cameras can take millions of images of proteins from countless angles and combine them into a 3D map.
On this map, researchers can create a 3D model of the protein and put each atom in its place. “It reminds me of solving puzzles,” explains Mancia. This technology has advanced in recent years thanks to Dr. Joachim Frank, a 2017 Nobel Prize-winning professor of biochemistry and molecular biophysics at Bageros Medical Surgery University at Columbia University, developed a very powerful technology for the visualization of biomolecules. I am. His role in developing data analysis algorithms for cryo-electron microscopes.
“Our structure shows that MFSD2A is shaped like a bowl and that omega 3 binds to certain aspects of that bowl,” explains Cater. “The shell is upside down and facing the inside of the cell, but this is a 3D snapshot of one of the proteins that actually needs to be moved to the next location. transport Omega 3. To understand exactly how it works, you need several different snapshots, or better still, a film of a moving van. “
To understand what these movements look like, George Khelashvili, Ph.D., Assistant Professor of Physiology and Biophysics at Weill Cornell Medicine, co-led the study. Uses a 3D model of the protein as a starting point for execution. A computer simulation showing how the transporter moves and adjusts its shape to release omega-3s into the brain. The third co-lead on this study, David Silver, Ph.D. Is a professor at Duke-NUS Medical School in Singapore and a pioneer in MFSD2A biology. He and his team are working on testing and confirming hypotheses derived from structural and computer simulations. How MFSD2A works to identify specific parts of important proteins.
The team also included researchers from the New York Structural Biology Center, the University of Chicago, and the University of Arizona, all of whom used specific skills to make this project possible.
The team is currently investigating how transporters first recognize omega-3s from the bloodstream. “But our study has already given us tremendous insight into how MFSD2A delivers omega-3s to the brain, and to see where our results are going. I’m really excited, ”says Kata.
Scientists use the natural transport system in their brain
For more informations:
Rosemary J. Kata et al., The Structural Basis of Omega-3 Fatty Acid Transport across the Blood-Brain Barrier, Nature (2021). DOI: 10.1038 / s41586-021-03650-9
Irving Medical Center at Columbia University
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