3D Structure Offers Insight into Inflammatory Diseases
New findings may improve drug development for autoimmune and inflammatory diseases.
In an effort to combat inflammation, investigators found that the 3D structure of CC chemokine receptor 2 (CCR2) simultaneously binds to 2 inhibitors, according to a study published in Nature.
CCR2 is a protein located on the surface of immune cells, which senses and transmits inflammatory signals that push cell movement toward inflammatory sites in the body.
This protein, and associated signaling molecules, are known to play a role in several inflammatory and neurodegenerative diseases, such as asthma, cancer, diabetic nephropathy, and multiple sclerosis. Although drug manufacturers have attempted to develop drugs that target CCR2, the treatments have yet to make it to market.
“So far drugs that target CCR2 have consistently failed in clinical trials,” said co-lead investigator Tracy Handel. “One of the biggest challenges is that, to work therapeutically, CCR2 needs to be turned off and stay off completely, all of the time. We can’t afford ups and downs in its activity. To be effective, any small molecule drug that inhibits CCR2 would have to bind the receptor tightly and stay there. And that’s difficult to do.”
CCR2 spans the membrane of immune cells, according to the study. A part of the receptor sticks outside of the cell, while the other half remains inside. Chemokines are inflammatory molecules that bind to the external part of CCR2, and the receptor carries that signal to the inside of the cell.
Once inside the cell, CCR2 changes shape and binds to other communication molecules, such as G proteins, triggering a cascade of activity, according to the study. This results in the immune cells beginning to follow chemokine trails that lead to areas of the body where help is needed.
To determine the 3D structure of CCR2, with 2 molecules bound simultaneously to it, the investigators used a technique called X-ray crystallography.
“Receptors that cross the cell membrane are notoriously hard to crystallize,” said co-lead investigator Irina Kufareva, PhD. “To promote crystallization, we needed to alter the amino acid sequence of CCR2 to make the receptor molecules assemble in an orderly fashion. Otherwise, when taken out of the cell membrane, they tend to randomly clump together.”
Additionally, the results of the study showed that the 2 small molecules binding CCR2 turn the receptor off by different, but mutually reinforcing mechanisms. One of the molecules binds the outside of the receptor, and blocks binding of the natural chemokines that normally turn the receptor on. The other molecule binds to the face of the receptor inside the cell, preventing inflammatory signal transmission. According to the study authors, this is the first time this binding site has been observed.
“It’s our hope that this new structure of CCR2 with 2 bound inhibitors will help optimize current and future drug discovery efforts,” Kufareva said.