Stanford University School of Medicine

* B.S., biochemistry, Tulane University
* Ph.D., biophysics, The Johns Hopkins University School of Medicine

The molecular mechanisms that a cell uses to monitor and relay information about its environment to its interior are not well understood. Cell surface receptors are the gateways through which this information is relayed. The activation of receptor molecules embedded in the cell’s membrane is fundamental to virtually every vital physiological function. Better knowledge of these mechanisms may lead to development of new disease treatments, using detailed structures of receptors complexed with their ligands as templates for engineering novel drugs.

K. Christopher Garcia is studying the structure and function of cell surface receptor recognition and activation in biological systems directly implicated in human health and disease. The receptor systems he studies are at the interface between immunity, neurobiology, and microbial pathogenesis. He focuses on “shared” receptors, which can recognize and bind to several different molecules, or ligands, often eliciting unique responses. Although this is a common phenomenon in biological signaling, until recently, researchers puzzled over how a single molecule could recognize so many different binding partners.

While others puzzled, Garcia pursued the question with extraordinary tenacity, bringing to bear his broad knowledge of many areas of science. Uniting structural studies of these receptors with biochemical and biophysical experiments, Garcia has identified new paradigms for recognition and activation of a variety of receptors that play critical roles in autoimmunity (T cell receptor and peptide-MHC), cancer (gp130 and cytokine receptors), neural growth and repair (p75 neurotrophin and Nogo receptors), and blood pressure regulation (ANP receptor).

Each of these receptors acts in a unique way. For example, the T cell receptor interacts with antigenic peptide and MHC in a manner representing the convergence of 400 million years of coevolution by our cellular immune system. Garcia and his colleagues determined the structure of the first complete TCR and its complex with peptide-MHC. Subsequent biophysical studies have shown that activation of the TCR is achieved through a complex combination of conformational change and kinetic discrimination. However, the precise molecular basis of TCR recognition and activation, as well as other lineages of immune receptors, remains a long-term challenge for the Garcia lab.

Another receptor binding paradigm elucidated by the Garcia lab is that of gp130—a growth factor receptor that is frequently aberrantly activated in disorders of the blood, such as leukemia. Its components cluster together in a precise temporal and geometric sequence, like pieces of a jigsaw puzzle, to assemble a receptor signaling complex. In contrast to the positive cooperativity exhibited by gp130 during signaling, the p75 neurotrophin receptor appears to induce a conformational change in its ligand, nerve growth factor, in order to prevent assembly of a higher order signaling complex. And the ANP receptor, which is crucial to the body’s response to high blood pressure, is activated by a large conformational change that does not require the assembly of multiple components.

Garcia’s long-term goal is to probe these systems more deeply, working to examine entire receptor molecules before and after activation, loaded with their full complements of extracellular ligands and intracellular adapter molecules. Understanding the many ways in which the relatively simple act of ligand binding prompts conformational change and ultimately activates receptors should help researchers design drugs targeting receptors whose functions affect human disease.

Dr. Garcia is also Associate Professor of Microbiology and Immunology and of Structural Biology at Stanford University School of Medicine.


K. Christopher Garcia studies the structure and function of cell surface receptor recognition and activation, in the immune and nervous systems.

Howard Hughes Medical Institute, November 18, 2007
K. Christopher Garcia, PhD

Despite extensive vaccination efforts, measles remains a dangerous, highly contagious disease worldwide, infecting some 20 million people a year. Structural information about the protein the virus uses to attach itself to its target cells could provide a new strategy to fight infection. A new structure from Howard Hughes Medical Institute (HHMI) researchers reveals important features of the propeller-like molecule, known as measles virus hemagglutinin (MVH), that drug designers will need to consider as they attempt to thwart infection by interfering with the virus’s grip on its host cell.

Researchers Leremy Colf and Sean Juo determined the structure in the laboratory of Howard Hughes Medical Institute investigator Christopher Garcia. The researchers published their findings November 18, 2007, as an advance online publication of the journal Nature Structural and Molecular Biology. They are at the Stanford University School of Medicine.

“Neuraminidases act as a kind of general molecular Velcro, sticking the virus to the surface of cells.”
K. Christopher Garcia

Colf and Juo employed X-ray crystallography to solve the structure of MVH. In this widely used technique, X-rays are directed through crystals of a protein, allowing the protein’s structure to be deduced from the diffraction pattern of the X-ray beam.

The resulting structure revealed that MVH is shaped like a propeller, with its blades spread such that they can attach to the host cell in the infection process. This propeller shape is commonly found on the surfaces of viruses as a protein called a neuraminidase. Viruses such as influenza use a cleft at the center of the propeller to bind carbohydrates on the cells they infect. “Neuraminidases act as a kind of general molecular Velcro, sticking the virus to the surface of cells,” said Garcia.

One feature that makes the measles virus unique is that it doesn’t use carbohydrates to bind to host cells. “While MVH exhibits the neuraminidase fold, it is a `dead’ neuraminidase, having lost all function,” he said. “Rather, the measles virus hemagglutinin has evolved the ability to bind to two non-overlapping host cell receptors, called SLAM and CD46. This is a completely novel mechanism for this class of viruses. So, if a drug is to block measles virus binding, it has to interfere with both of these receptors.”

Garcia said that the structure of MVH provides “a starting point to identifying cavities and clefts on the protein surface that one could target with small molecules.” The next step, he said, is to solve the structure of MVH complexed with the host cell receptors, to elucidate the details of the host-virus attachment. So far, his group has begun to analyze the structure of MVH complexed with the SLAM receptor.

“Once we have high-resolution pictures of the determinants of this attachment interface, it will be possible to begin to think about therapeutic intervention in that attachment,” he said.