NIH Common Fund Researchers Uncover Structure of Important Target for Drug Design
The S1P1 receptor is a type of receptor in cells that can be targeted in the design of new treatments for diseases such as multiple sclerosis.Structural biology is a field of study aimed at determining the molecular structure of biological molecules, such as proteins, and how alterations in their structures affect their function.
The ability to determine how well different drugs bind to a protein receptor to turn on or turn off the receptor provides a powerful way to design new drugs that selectively target certain receptors and not others, a major stumbling block to drug development.
"This work is an excellent example of how structural studies can reveal insights into basic principles of protein function and how this may lead to smarter, safer drugs,” said NIH Director Francis S. Collins, M.D., Ph.D.
Collins continued, "This approach could be used to design better therapies for a variety of adverse health conditions."
G-protein coupled receptors (GPCRs) comprise a highly diverse class of protein receptors that are common targets of therapeutic interventions due to their central roles in multiple normal and pathological processes.
GPCRs reside on the surface of cells and are activated by binding select molecules. The sphingosine 1-phosphate 1 (S1P1) receptor is a GPCR that is activated by certain fat molecules.
Its role in the immune response has made it an attractive therapeutic target for multiple sclerosis, a disease where the body's own immune system attacks and damages nerve cells.
However, S1P1 is so similar to several other GPCRs that modifying its function selectively without affecting other receptors has proven difficult.
Using technology developed through the Structural Biology Program of the NIH Common Fund, established through the NIH Reform Act to support innovative, trans-NIH programs, along with the NIGMS-funded Protein Structure Initiative (PSI), the research teams of Drs. Raymond Stevens, Ph.D., and Hugh Rosen, M.D., Ph.D., of The Scripps Institute teamed up to take molecular snapshots of S1P1 bound to different activators and inhibitors developed through the Common Fund's Molecular Libraries and Imaging Program.
The snapshots revealed that S1P1 has structural features that allow it to bind activators in two ways. One of these structural features varies subtly between related GPCRs, such that molecules can be designed to activate S1P1 selectively.
Such molecules may prove to be effective therapies for multiple sclerosis with fewer side effects than current therapies.
“The potential impact of this research is far-reaching, since members of the GPCR family have been implicated in a wide range of diseases, including heart disease, allergy and multiple sclerosis,” said James M. Anderson, M.D., Ph.D., director of the Division of Program Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund’s programs.
Anderson continued, “Using the results from this study, investigators may be able to design drugs that selectively activate or inhibit other important GPCRs.”
“This innovative work reflects the deep integration of chemistry and biology at The Scripps Research Institute,” said Michael A. Marletta, Ph.D., president of Scripps Research.
Marletta continued, “The close collaboration among our scientists in different disciplines makes studies with far-reaching results like this possible.”
The NIH Common Fund supports a series of exceptionally high impact research programs that are broadly relevant to health and disease.
Common Fund programs are designed to overcome major research barriers and pursue emerging opportunities for the benefit of the biomedical research community at large.
The research products of Common Fund programs are expected to catalyze disease-specific research supported by the NIH Institutes and Centers.
The Common Fund's Structural Biology Program is developing novel approaches to isolate membrane proteins and characterize their 3D structure while the Molecular Libraries and Imaging Program supports large-scale screening efforts to identify small molecules that facilitate studies of biological processes in health and disease.
Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.
“This fundamental advance would not have been possible without NIH Common Fund’s far-sighted vision and support of these two programs,” said Rosen, who is principle investigator of the Scripps Research Molecular Screening Center, part of the NIH Molecular Libraries and Imaging Program.
Rosen continued, “The programs have come together to contribute to a more efficient data-enabled approach to therapeutics. One compound resulting from the NIH Molecular Library is already in clinical trials for the treatment of multiple sclerosis and other autoimmune diseases.”
The PSI is a continuing effort to improve the efficiency of three-dimensional protein structure determination, especially the structures of difficult targets such as membrane proteins.
It is funded by NIGMS, a part of NIH that supports basic research to increase our understanding of life processes and lay the foundation for advances in disease diagnosis, treatment, and prevention.
These findings are reported in the Feb. 17 issue of the journal Science.
The research was supported by the National Institutes of Health Common Fund and the National Institute of General Medical Science (NIGMS).