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MILESTONE SYMPOSIA
Symposium Highlights Molecular Architecture and Cellular FunctionMotion was the prevailing theme of the symposium honoring the 100th anniversary of the groundbreaking for the Longwood Quadrangle. Held in the new research building, five talks showcased how direct structural approaches are making inroads into some longstanding problems in membrane biology, such as how viruses, ions, and nutrients enter and exit cells.
Roderick MacKinnon (left), cowinner of this year's Nobel Prize in Chemistry, gave the keynote talk at the symposium launching the new HMS Center for Molecular and Cellular Dynamics, a research initiative headed by Stephen Harrison. The symposium was the first in a series of six celebrating the 100th anniversary of the Longwood Quadrangle groundbreaking. (Photo by Liza Green, HMS Media Services) The symposium officially launched the new HMS Center for Molecular and Cellular Dynamics, a research initiative that seeks to reveal fresh avenues of medical intervention by turning static images of molecules into "movies" of fully functioning molecular machines (see Focus, Jan. 24, 2003). An anonymous $1 million gift from an individual donor kicked off the center's fund-raising campaign. Heights of Structural BiologySpace on the South Quad that is vacated by researchers moving into the new research building will allow HMS to grow and strengthen structural biology and other activities, said HMS dean Joseph Martin, who moderated the symposium."People say that structural biology is mature, but it's actually coming into its most exciting era," said keynote speaker Roderick MacKinnon, the John D. Rockefeller Jr. professor at Rockefeller University, a Howard Hughes Medical Institute investigator, and cowinner of the 2003 Nobel Prize in Chemistry, which was announced Oct. 8. "It's clear that it will be exciting at Harvard for a long time to come."
Center director Stephen Harrison, HMS professor of biological chemistry and molecular pharmacology and HHMI investigator, opened the morning by discussing two ways that proteins can move across membranes: membrane fusion and protein-conducting channels. "The point of understanding these elaborate physical interactions is to uncover new opportunities for intervention and focus on them," Harrison said. One proof of concept of interfering with the viral fusion protein has come in the form of a recently licensed HIV drug. Membranes can fuse together. This process is how "enveloped" viruses like HIV, influenza, and West Nile enter cells. When the virus senses its target cell, a fusion protein on its surface inserts itself into the cell membrane and folds back nearly inside out to merge the two membranes and dump the viral genes into the cell, Harrison said. In new unpublished work, the rearranged, postfusion shape of the dengue fusion protein may reveal both a new potential strategy for inhibiting viral entry and fundamental knowledge about more general viral fusion mechanisms. (In May, postdoctoral fellow Yorgo Modis and Harrison reported a potential ligand-binding pocket in the prefusion structure. See Focus, June 6, 2003). In a change of scale, Jon Clardy, HMS professor of biological chemistry and molecular pharmacology, talked about the close link between chemical and structural biology. Gathering the DirtAntibiotics, anticancer drugs, and many other medically useful molecules come from the most genetically diverse organisms on the planet, bacteria. Unfortunately, most bacteria have eluded scientists' attempts to culture them in the lab."It's the dirt under our feet, and we don't even get a statistically significant portion," Clardy said. "That's a substantial bottleneck. There are two to three orders of magnitude more new interesting natural products to be discovered than we have discovered so far." Even the human mouth has about 300 organisms that have not yet been cultivated, observed an audience member. Clardy and his colleagues extract DNA directly from the soil--so far, mostly from a swampy area around a pond in Ithaca, N.Y.--and express potential genes in host E. coli bacteria. Recently, in pursuit of novel antibiotics, Clardy found a molecule, FeeM, which may be a catalyst for a new kind of signaling pathway, according to clues suggested by comparative genetic and structural analysis. Clardy's group is also working to develop alternative hosts to expand the variety of genes that can be expressed. Caught in the ActThe most abundant element on Earth, iron, can be toxic to the organisms that need this essential element, because it can turn life-giving oxygen molecules into destructive free radicals. In blood, iron is safely transported by the molecule transferrin. Iron-loaded transferrin binds to a receptor. This complex enters the cell through a structure known as a coated pit, which pinches off from the cell surface and fuses with an endosome, where the low pH loosens the iron. Another vesicle carries the empty transferrin, still bound to its receptor, back out into the blood. For the first time, Tom Walz, HMS assistant professor of cell biology, has captured an image of the elusive structure of iron-loaded transferrin in contact with the cell receptor. Led by HMS research associate Yifan Cheng, their electron microscopy technique produced an unusually detailed look at the small complex. The report is under review for possible publication.Pamela Bjorkman, professor of biology at the California Institute of Technology and HHMI investigator, provided a progress report on her latest attempts to find out how maternal antibodies enter the bloodstream of mammalian fetuses, which are born without fully functional immune systems. Human placentas have FcRn receptors that bind IgG antibodies in the acidic pH of intracellular endosomes and release them in the basic pH of the bloodstream. Bjorkman wants to see what it looks like in action. The same receptor protects serum antibodies from degradation. The receptor has a nearly identical structure to the MHC I molecule she worked on as a postdoctoral fellow in the Harvard lab of Don Wiley, Harrison's close collaborator, who died two years ago. Bjorkman is pursuing a technique in electron microscopy, electron tomography, to obtain a three-dimensional reconstruction of the combined receptor-antibody structure as it travels inside a vesicle in the cell. MacKinnon described several years of research and analysis trying to understand how potassium channels select the proper ions and move them at high speeds, how the channels open and close, and how certain channels open and shut in response to membrane voltage. Biology has set up a system of pumping ions up a concentration gradient and letting them run back down by diffusion, MacKinnon said. In one part of the emerging story, a potassium ion fits perfectly into tailored "cages" that have a familiar waterlike arrangement of oxygen molecules. Because they repel each other, two ions are barely tolerable company for each other in the four-cage channel. Approach of a third ion in the queue pushes the first one through rapidly. MacKinnon concluded his talk with a discussion of channel gating in response to membrane voltage. MacKinnon's most recent work gives a first approximation of the molecular mechanism of voltage gating. The next topic in the six-symposium series is "The Cell Cycle and Cancer," from 8:30 a.m. to 12:30 p.m. on Oct. 23. For more details, see www.hms.harvard.edu/milestone. --Carol Cruzan Morton |
