Scripps Research Scientists Win $65 Million in New Grants

By Mika Ono

Scripps Research Institute scientists have been awarded approximately $65 million in four five-year grants as part of the National Institutes of Health's (NIH) latest round of structural biology funding. The projects will focus on determining the shapes and functions of proteins and protein complexes that are important in biology and medicine.

"The grants are an acknowledgement of The Scripps Research Institute's leadership in the field of structural studies," said Scripps Research President Richard A. Lerner. "We're looking forward to many more important advances from our scientists thanks to this latest round of support from the NIH."

The four Scripps Research grants are part of the NIH Protein Structure Initiative (PSI), an effort that started in 2000 with the main goal of developing highly efficient methods for solving the structures of many different proteins. The new grants mark the beginning of the effort's third phase, called "PSI:Biology." A key aim of this phase is to apply the high-throughput methods developed during the initiative's first decade to challenging biological problems and systems.

"These awards to Scripps Research represent the key elements of the Protein Structure Initiative—from generating structures and new structure determination methods for particularly challenging proteins to harnessing the power of high-throughput to address important biological problems," said Ward Smith, Ph.D., director of the PSI. "Together, these approaches can significantly advance our understanding of the role proteins play in health and disease."

The Scripps Research grants are:

• $37.6 million to a consortium led by Ian A. Wilson, Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at Scripps Research.
• $5.8 million to a group led by Jamie Williamson, professor, dean of the graduate school, and member of the Skaggs Institute, and Daniel R. Salomon, associate professor and Medical Director of the Scripps Center for Organ and Cell Transplantation
• $16.8 million to a center led by Raymond Stevens, professor in the Departments of Molecular Biology and Chemistry, together with Scripps Research investigators Assistant Professor Vadim Cherezov, Associate Professor Peter Kuhn, Professor Hugh Rosen, and Professor Kurt Wüthrich
• $5 million to the Scripps Research portion of a collaboration led by Geoffrey Chang, associate professor and member of the Skaggs Institute, in conjunction with Doug Rees, Howard Hughes Medical Institute investigator and Professor at the California Institute of Technology, and Michael Stowell, associate professor at the University of Colorado. The total for this grant is $11.5 million.

Large-Scale Structure Determination

Building on a decade of success and the solution of more than 1,000 structures, Wilson will continue to lead one of four, long-standing, large-scale PSI centers.

The consortium—called the Joint Center for Structural Genomics (JCSG) and comprising scientists at the University of California, San Diego; Genomics Institute of the Novartis Research Foundation (GNF); Sanford-Burnham Medical Research Institute; and Stanford Synchrotron Radiation Lightsource (SSRL), Stanford University—will continue to operate its pipeline for high-throughput structure determination. Structures that the group plans to tackle over the next five years include challenging targets, such as eukaryotic proteins, as well as protein-protein, protein-RNA, protein-DNA, and other complexes.

One theme of the center's research will be the human "microbiome," the totality of microbes in a defined environment, such as the human digestive tract.

"Interactions of bacteria with the human body are profound and have a significant impact on maintenance of general human health," said Wilson. "In addition, they are associated with obesity, inflammatory diseases, diabetes, and certain cancers, to name but a few disorders."

The center will focus on solving these structures by continuing to hone their highly efficient methods and by conducting collaborative research, including with scientists outside the PSI network.

Biological Problems

The JCSG and other large-scale centers will partner with eight groups of biologists, including one based at Scripps Research, that require the determination of many protein and protein-RNA structures to understand biological processes or a molecule's function.

The Scripps Research center, led by Williamson and Salomon, will focus on better understanding the workings of part of our immune system, which protects us against disease by fending off pathogens such as bacteria, viruses, and tumor cells. The immune system is also a critical determinant of the success or failure of kidney, heart, liver, and bone marrow cell transplants. In particular, the scientists aim to better understand the role of ribonucleoproteins (complexes of RNA and protein involved in a wide range of cellular processes, including protein synthesis) in regulating the activation of T-cells, a type of white blood cell.

"This work should provide significant new insights into the structure of ribonucleoprotein complexes in general," said Williamson. "In addition, we hope to gain new insights into how these complexes are involved in posttranscriptional gene regulation."

"Understanding how T cells draw from all the information embedded in the human genome to determine how to respond to an immune challenge like a virus, tumor cell, or transplant is an opportunity to study the mechanisms of health and disease," added Salomon, "and to do this at the level of protein structures in this new collaboration with the JCSG is a remarkable opportunity to advance translation biology and medicine."

The scientists will use genomic, biochemical, and functional research in combination with structural studies to forge new inroads in the field.

Membrane Protein Structures

The new grants also support nine centers—two of which are based at The Scripps Research Institute—for determining membrane protein structures. Membrane proteins, which are embedded in the membranes of our cells, are important because they enable our nerves, muscles, and even hormones to do their jobs. Currently, however, scientists can't easily visualize their three-dimensional shapes to understand how these proteins function.

The Scripps Research Institute center led by Stevens, Cherezov, Kuhn, Rosen, and Wüthrich will focus on a special class of human membrane proteins called G protein-coupled receptors (GPCRs), signaling molecules that span the membranes of cells, "sensing" chemical messages outside the cells and converting them into action within the cell. GPCRs are the largest family of proteins in the human genome.

"Our fundamental understanding of GPCR molecular recognition and signaling is still in the early stages," said Stevens. "Through the creation of the GPCR Network center, we will work directly with the GPCR community on improving our basic understanding of receptor structure and function using a variety of biophysical techniques including NMR, HDX, and X-ray crystallography, as well as computational and chemical screening techniques. Only a few GPCR structures in their inactive state have been solved to date and the basic understanding of this key membrane protein class will change drastically in the next five years with the NIH funding."

In a separate group, Chang, Rees, and Stowell will focus on a class of proteins called transporters—a type of large protein that resides in the cell membrane and moves other molecules in and out. Transporters are vital to the biology of all cells and a variety of diseases occur when these processes are perturbed or disrupted, as in several genetic disorders. In addition, cancer cells resist chemotherapy by using these transporters, and bacterial cells use them to resist antibiotics.

"We actually have very good drugs to fight cancer and to kill bacteria," said Chang. "[But] they can't always get into the cells to work."

This new center, dubbed TransportPDB, aims to develop a comprehensive and efficient approach for pursuing the high-resolution x-ray crystal structures of several transporters that PSI scientists have selected as important in biomedicine.

Send comments to: mikaono[at]scripps.edu

— Richard A. Lerner