3-D Structure of Chemokine Receptor Facilitates Drug Discovery

A new chemokine receptor study offers new drug development approaches for autoimmune and inflammatory diseases.

Inflammation reactions in our bodies fight against infections; however, too much of these reactions may result in cancer or autoimmune diseases.  To reduce inflammation, scientists rely on CC chemokine receptor 2 (CCR2), a protein which plays a significant role in inflammation. CCR2 binds on the immune cells like an antenna and senses and transmits inflammatory signals that stimulate cellular movement towards inflammation sites.

A team of researchers at the Pharmaceutical Sciences at University of California San Diego and the Skaggs School of Pharmacy have determined the 3D structure of CCR2 with two inhibitors.

Analyzing how these molecules bind with each other could be a potential target to create anti-inflammatory medicines that could bind and block CCR2 in the same way.

CCR2 and related signaling molecules play major roles in many inflammatory diseases and neurodegenerative disorders such as cancer, multiple sclerosis, diabetic nephropathy and asthma. Many pharmaceutical companies have tried to produce drugs which block CCR2, though not one are available in the market till date.

Tracy Handel, PhD, one of the lead authors of this study who serves as a professor in the Skaggs School of Pharmacy said, Up to now, that target CCR2 has always failed in clinical trials. To work as a therapeutic agent, CCR2 should be turned off entirely, all the time. We can't manage the ups and downs of CCR2 activity. To be efficient, any drug molecule that blocks CCR2 should fit the receptor firmly and stay there, which is a hard thing to do.

The study was led by Irina Kufareva, PhD, project scientist at Skaggs School of Pharmacy, and Laura Heitman, PhD, of Leiden University. The first author of the study, Yi Zheng, PhD, is a postdoctoral researcher at Skaggs School of Pharmacy.

CCR2 covers the membrane of immune cells. CCR2 has two parts, one of which binds outside the cell and another binds inside. Chemokines, which are inflammatory molecules, stick to the outer part of CCR2, after which the receptor transmits a signal to the inner part of the cell. In the interior part of the cell, CCR2 modifies shape and attaches to other interaction molecules such as G proteins, further stimulating a series of activities. In the end, the immune cells will be in motion, following the chemokine path that directs them to areas in the body where help is required.

For this study, the researchers used the X-ray crystallographic technique to find out the 3D structure of CCR2, along with the structures of two molecules that bind to it all together — one at both end.

According to Kufareva, It is difficult to crystallize receptors out of the cell membrane. To enhance crystallization, we have to modify the amino acid sequence of CCR2 to compose the receptor molecules assembly in a regular manner. If not, when taken out of the cellular membrane, receptors have a tendency to randomly cluster together. ”

Handel, Kufareva and the rest of the team also found that the two small molecules attaching CCR2 keep the receptor “off” by different but commonly supporting mechanisms. One of the small molecules attaches the outer region of the receptor and inhibits binding of the natural chemokines that usually turn the receptor “on.” The other small molecule attaches to the surface of the receptor inside the cell, where the G protein usually binds, and blocks inflammatory signal transmission. Handel mentioned that the latter binding location has never been noted before.

Kufareva said, We hope that this new CCR2 structure with two inhibitors will be helpful in optimizing present and future drug discovery efforts.