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Scientists solve structure of key protein in innate immune response

When bacteria invade the body, a molecule called CD14 binds to substances liberated from the bacteria and initiates the cellular defense mechanisms. In a report published in the Journal of Biological Chemistry, scientists in Korea announced their elucidation of three-dimensional structure of CD14 and showed how it is perfectly suited to bind to certain bacterial products.

The research appears as the "Paper of the Week" in the March 25 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

The innate immune system uses the CD14 receptor protein to recognize several microbial and cellular products including lipopolysaccharide (LPS), a glycolipid found on the outer membrane of certain bacteria. Once CD14 binds to LPS or another ligand, it presents the molecule to other proteins which initiate a strong pro-inflammatory response that stimulates host defenses.

"Macrophages and monocytes can recognize distinct structural patterns in various molecules from pathogenic microorganisms," explains Dr. Jie-Oh Lee of the Korea Advanced Institute of Science and Technology. "LPS is the most famous and probably the most important inducer of the innate immune response."

Dr. Lee and his colleagues solved the three-dimensional crystal structure of CD14, providing crucial insights into how the receptor binds to its ligands. "Our structure shows that CD14 has a large hydrophobic pocket near its amino terminus," says Dr. Lee. "We propose that this pocket is the main binding site for LPS because previous biochemical studies demonstrate that amino acid residues comprising the pocket are critical for LPS binding. Most, if not all, of the CD14 ligands compete with LPS for CD14 binding. Therefore, they probably share the same binding pocket with LPS."

Ligands other than LPS can be accommodated in the pocket due to its large size, the flexibility of its rim, and the multiple grooves available for li gand binding. The researchers also discovered that mutations that interfere with LPS signaling cluster in a separate area near the pocket suggesting that the areas around the pocket are important in LPS transfer.

Not only do these findings shed light on how cells recognize pathogens, they also may also lead to the development of drugs to help treat septic shock, an often fatal systemic bacterial infection that is triggered by LPS.

"Pharmaceutical companies have tried to develop anti-septic shock agents for a long time without clear success," explains Dr. Lee. "Since LPS is an important inducer of septic shock, blocking LPS receptors such as CD14 are among the most important targets. Our structure shows the shape of the LPS binding pocket of CD14. Now, drug developers will have better chance to design a molecule that will complement the shape of the pocket."


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Source:American Society for Biochemistry and Molecular Biology


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