News and Publications

Chairman's Overview

Peter E. Wright, Ph.D.

Research in the Department of Molecular Biology encompasses a broad range of activities, extending from molecular genetics through RNA and protein engineering to structural biology. Our scientists continue to make exciting progress toward understanding the fundamental molecular events involved in control of the cell cycle, regulation of transcription, decoding of genetic information in translation, folding of proteins into biologically active states, and structural biology of signal transduction and viral assembly. Advances are being made in elucidating the molecular basis of RNA and DNA recognition by proteins, understanding mechanisms of viral infectivity and of catalysis by ribozymes and enzymes, determining the mechanism of action of sleep-inducing neuropeptides, and engineering novel functions into proteins and RNA. Progress in all these areas is described in detail on the following pages.

Among the many exciting discoveries of the past year, a few deserve special mention. John Tainer and Elizabeth Getzoff and their colleagues determined the first 3-dimensional structure of the protein domain containing the catalytic center of nitric oxide synthase. Nitric oxide plays a key role as a signal transducing molecule in processes such as regulation of blood flow, neurotransmission, and memory and also functions as a defensive agent against tumor cells and pathogens. Determination of the structure of nitric oxide synthase is therefore a major step toward understanding the mechanism by which nitric oxide is produced and regulated in mammalian cells. The synthase is also an extremely important drug target, and the structure provides a critical template for the design of novel inhibitors.

Another structure solved during the past year sheds new light on mechanisms of peptide recognition by the T-cell receptor. The central event in immune responses mediated by T cells is the discrimination between self-peptides and peptide antigens from foreign pathogens. This discrimination is accomplished by the T-cell receptor in conjunction with MHC molecules. Ian Wilson and Christopher Garcia and their colleagues have now determined the structure of a T-cell receptor bound to a self-peptide--MHC complex. The structure reveals the molecular basis by which the receptor can scan self and foreign peptide antigens bound to the MHC and discriminate between the two antigens.

Despite the atomic resolution structures available for many viruses, understanding of the dynamic nature of the viral surface remains limited. Gary Siuzdak and Jack Johnson and their colleagues have now developed a novel method that uses mass spectrometry to obtain previously unavailable information about the dynamic nature of the viral surface. These studies promise to provide new insights into the structural changes involved in cell binding, membrane penetration, and nucleic acid release during viral infection.

The genomes of many organisms are being sequenced at a rapid rate, yielding vast quantities of sequence data. Making use of that data to determine the biological function of the numerous proteins encoded by those genomes remains a major challenge. Jacquelyn Fetrow, Adam Godzik, and Jeffrey Skolnick have developed a new computational method for determining protein function. The new method uses threading techniques to identify proteins with similar folding topologies and conserved active-site residues. It is readily automated and can be applied to analysis of complete genome databases. The ability to rapidly screen genome sequences to determine biological function is an important advance toward efficient use of genome data in biology and medicine. In a separate advance that provides unique insights into the molecular events that occur during protein folding, Jane Dyson, Peter Wright, and their coworkers have used nuclear magnetic resonance methods to map the changes in backbone structure and dynamics that accompany compaction of polypeptide chains. These data provide the first high-resolution view of the structure and dynamics of a protein-folding intermediate.

A major activity in several laboratories involves engineering novel functions and activities into proteins or RNA. Using the method of reactive immunization, Richard Lerner, Carlos Barbas, and their colleagues have generated an antibody that can efficiently catalyze a broad range of reactions, of more than 100 different substrates, that proceed by the aldol mechanism. Because of its high efficiency and broad scope, this aldolase antibody is the first catalytic antibody to enter commercial use. Structural and chemical characterizations are providing important insights into the similarities and differences between this engineered protein catalyst and its natural enzyme counterpart and into the evolution of enzyme activity.

The recognition that some biochemical reactions are catalyzed by RNA rather than by proteins has led to a whole new field of enzymology. Until recently, it was thought that all catalytic RNA molecules, or ribozymes, recruited metal ions to carry out the catalysis. That view must now be revised, because Martha Fedor and coworkers have established that the hairpin ribozyme requires no metal ions for its catalytic activity. This finding raises the exciting possibility that functional groups on the RNA itself participate directly in the chemistry of catalysis.

As will be clear from these few highlights and from the detailed reports on the following pages, the field of molecular biology is one of great excitement and opportunity. Our scientists are taking full advantage of these opportunities to advance our understanding of fundamental biological processes and to pave the way for future advances in medicine.