A Trio of Accolades

What do photosynthesis, potassium transport, and protein production have in common? Revealing the structures of molecules central to each of these processes yielded a Nobel Prize for three HHMI investigators.

Johann Deisenhofer, an HHMI alumnus investigator at the University of Texas Southwestern Medical Center, won his Nobel the same year he joined HHMI, just two years after the Institute launched its program in structural biology. He shared the 1988 Nobel Prize in Chemistry with Robert Huber and Hartmut Michel for work they did at Germany’s Max Planck Institute for Biochemistry. They were the first to solve the structure of a membrane-bound protein, the photosynthetic reaction center.

Plants and some bacteria use photosynthesis to convert the sun’s rays into the chemical energy that fuels their activities. The process occurs in the photosynthetic reaction center—a cluster of proteins, pigments, and cofactors nestled in bacterial membranes and in plant organelles called chloroplasts. Chlorophyll, the pigment that gives plants their green color, captures sunlight and spits out electrons, which are passed from one reaction center protein to another, eventually resulting in the production of ATP.

Deisenhofer, Huber, and Michel spent more than four years working on the crystal structure of the photosynthetic reaction center from the purple bacteriumRhodopseudomonas viridis. The final structure, at more than 10,000 atoms, was then the largest molecular complex ever characterized. They discovered the reaction center is composed of four protein subunits, two of which form clusters of alpha-helices that zigzag across the membrane. By pinpointing the locations of the photochemically active groups and the reaction center proteins, the scientists were able to deduce how electrons are shuttled across the bacterial membrane to create ATP. Knowing the structure also allowed them to draw parallels to photosynthesis in plants and gain insights into membrane-bound proteins, which are crucial to the functioning of enzymes, hormones, and other proteins in the body.

HHMI investigator Roderick MacKinnon’s Nobel Prize–winning work also involved a membrane protein. Using x-ray crystallography, the Rockefeller University scientist solved the structure of the potassium channel, a membrane-spanning pore that selectively allows potassium ions to pass through the membrane. The channels are involved in electrical signaling in the body, playing essential roles in the nervous system.

MacKinnon’s potassium channel structure from the bacterium Streptomyces lividan revealed that the molecule contains four identical subunits assembled in the shape of an inverted teepee. This configuration, and the presence of a group of water-excluding amino acids, is the key to the channel’s selectivity, allowing only potassium to pass through and excluding much smaller sodium ions. Both potassium and sodium travel through cells bound to water molecules. When they enter the wide end of the channel, they encounter a selectivity filter, which, MacKinnon found, lets potassium but not sodium shed its coat of water. The potassium ion then squeezes through the narrowing tunnel while the water-bound sodium is left behind.

MacKinnon shared the 2003 Nobel Prize in Chemistry with Peter Agre of the Johns Hopkins University School of Medicine, who discovered the water channel, another type of selective membrane pore that allows passage of only water molecules.

Six years later, HHMI investigator Thomas Steitz of Yale University won a Nobel Prize for helping solve the structure of one of the largest and most complex cellular machines—the ribosome.

Weighing in at more than 150,000 atoms, the ribosome is an intricate arrangement of RNA and protein. The complex is the primary site of protein synthesis, where single amino acids string together to form biologically functional molecules. The ribosome consists of two pieces—a large subunit and a small subunit. Concentrating on the large subunit from the bacterium Haloarcula marismortui, Steitz and his colleagues spent almost five years investigating its structure by x-ray crystallography. Their atomic map showed an outer shell of 31 proteins surrounding 3,000 bases of coiled RNA. This RNA core turned out to be the production center for the machine—the place where protein synthesis occurs. The discovery shattered the notion that proteins had to be built by other proteins and bolstered the theory that the Earth’s first organisms were assembled from RNA.

Steitz earned one-third of the 2009 Nobel Prize in Chemistry for his work on the large subunit. He shared the prize with Venkatraman Ramakrishnan of the MRC Laboratory of Molecular Biology in England, who decoded the smaller subunit, and Ada Yonath of the Weizmann Institute of Science in Israel, who developed basic techniques for studying the ribosome.

In their Nobel-winning research, Deisenhofer, MacKinnon, and Steitz used three very different structures with distinct functions. Yet, all three HHMI investigators had one thing in common. They used the tools of structural biology to make discoveries that radically enhanced our understanding of how cellular proteins work.

-- Nicole Kresge
HHMI Bulletin, Winter 2013

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