Binding Studies Suggest Drug Development Strategy for Lupus

Tall-1 structure

Gongyi Zhang

Researchers at National Jewish Medical and Research Center have figured out how Tall-1, a protein implicated in the disease lupus, binds to its main receptor, Baff-R. The findings suggest that a small fragment of the Baff-R receptor could be developed as a treatment for lupus and other autoimmune diseases. The researchers report their findings in the May 1 issue of the journal Nature.

“Our structural studies have revealed a small section of the Baff-R receptor that is crucial to binding the Tall-1 molecule and triggering the maturation of B cells,” said Gongyi Zhang, Ph.D., Assistant Professor in the Integrated Department of Immunology at National Jewish and the University of Colorado Health Sciences. “This fragment is a good candidate for drug development because we believe such a small molecule would be easy to synthesize and to get into the body where it could bind to and neutralize Tall-1.”

The Tall-1 molecule is an important regulator of the immune system. It spurs B cells to mature and produce antibodies, one of the body’s major defense mechanisms. Mice engineered to make too much Tall-1 develop lupus-like symptoms. People with lupus and rheumatoid arthritis have been shown to have high levels of Tall-1 in their blood. Lupus and rheumatoid arthritis are autoimmune diseases in which the body’s immune system mistakenly attacks its own tissues. Approximately 1.4 million people in the United States, mostly women, suffer from lupus. Rheumatoid arthritis afflicts approximately 2.1 million people in the U.S.

The structural studies revealed that Baff-R sits on Tall-1 in a saddlelike manner. Tall-1 has a small hump with valleys on each side. Baff-R sits on the hump with its two binding domains extending into the valleys on Tall-1.

Dr. Zhang and his colleagues believe that a short section of one binding domain on Baff-R holds promise for drug development. Since the fragment binds to Tall-1, it might be able to prevent Tall-1 from binding to Baff-R and thus prevent it from triggering the signal for B cell maturation that seems to contribute to lupus and other autoimmune diseases. Patent applications are pending for use of this binding information to develop new medications.

In their paper, Dr. Zhang and his colleagues also reported how Tall-1 binds to another receptor, BCMA, whose function is unknown, but does not seem required for B-cell maturation. With the binding information from these two receptors and structural information about Tall-1 from previous work, the researchers also discovered why Baff-R binds to Tall-1, but not to the closely related protein, known as APRIL.

National Jewish Medical and Research Center is a nonprofit, Nonsectarian institution dedicated to enhancing the prevention, treatment and cures of respiratory, allergic and immune system diseases, including asthma, tuberculosis, emphysema, severe allergies, lupus, and other autoimmune diseases.

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