The folding of strings of amino acids into intricate, three-dimensional proteins is one of nature's most awesome mysteries. Indeed, the proper functioning of the body depends on proteins assuming precisely folded shapes. For more than 20 years, Johann Deisenhofer has used x-ray crystallography to study protein structure, with the goal of understanding how proteins fold and how their configuration determines their function.
In the 1980s, early in Deisenhofer's career, he and his colleagues at the Max Planck Institute for Biochemistry in his native Germany reached a milestone in structural biology research. Using x-ray crystallography—a tool that involves bombarding protein crystals with x-rays and then deducing the structure of the protein by analyzing the diffraction pattern produced by the x-rays—they were the first to unravel the atomic structure of a membrane-bound protein.
This particular protein, called the photosynthetic reaction center, is vital to the process of photosynthesis, on which all higher forms of life depend. For their work, Deisenhofer, Robert Huber, and Hartmut Michel were awarded the 1988 Nobel Prize in Chemistry. "It was truly a unique moment for me when I produced the big picture on the computer screen," Deisenhofer recalled. "This picture answered for the first time many questions about the folding and rearrangement of protein subunits and cofactors. Some of the structural features were entirely unexpected, and I was the first to see this. It was an incredible experience, and I was so excited that I could hardly sleep for the next few nights."
Their discovery, made in photosynthetic bacteria, has not only helped scientists understand more fully the process of photosynthesis in plants, but also has had important implications for understanding membrane-bound proteins, which are crucial to the functioning of enzymes, hormones, and other proteins in the body.
Deisenhofer's achievements in the laboratory might never have materialized had his parents not been willing to put his dreams ahead of their own. He grew up on his family's farm in Bavaria and, according to local custom, as the oldest son, he would one day take over its operation. But much to his parents' dismay, Deisenhofer showed little interest in farming, and his parents ultimately made the difficult decision to send him away to school. At the Technical University Munich, he was drawn to physics, mostly because of a penchant for astronomy aroused by reading popular books on the subject. Deisenhofer's interest eventually shifted to biophysics, his curiosity piqued by a professor who frequently spoke about the enormous potential of this field of research.
Today, in his laboratory at the University of Texas Southwestern Medical Center at Dallas, Deisenhofer continues to use x-ray crystallography to study proteins and other large macromolecules. He and his colleagues recently used the technique to better understand how the body normally regulates the buildup of bad cholesterol, known as LDL (low-density lipoprotein), by constructing a three-dimensional image of the LDL receptor. While cholesterol is an essential component of cell membranes and vital to life itself, elevated levels of LDL in the blood can lead to atherosclerosis and other health problems.
In related work, they have used x-ray crystallography to show how six different cholesterol-lowering drugs called statins fit into the active site of the enzyme HMG-CoA reductase, which catalyzes a key step in cholesterol production. Deisenhofer and his team also are working to understand how alterations in the amino acid sequence in critical regions of the LDL receptor might cause familial hypercholesterolemia, a common inherited disease marked by high cholesterol levels, atherosclerosis, and increased risk of heart attack early in life.