Molecular Structures Provide Insights Into Larger Questions In Biology

Editor's Note: This is the second part of a two-part series on the field of structural biology. Part 1, presented in the Aug. 22, 1994, issue of The Scientist (page 14), discussed the evolution of this booming discipline. This article focuses on structural biology's key areas of basic and applied research and looks ahead to its future. Following are some of the professional organizations whose memberships include structural biologists: American Chemical Society 1155 16th St., N.W. Washington, D.C. 20036 (202) 872-4600 Fax: (202) 872-4615 Ned Heindel, president John K. Crum, executive director American Crystallographic Association P.O. Box 96, Ellicott Station Buffalo, N.Y. 14205-0096 (716) 856-9600 Fax: (716) 852-4846 E-mail: acamjv%mfb@ubvms.cc.buffalo.edu Elinor Adman, president William L. Duax, executive officer American Society for Biochemistry and Molecular Biology 9650 Rockville Pike Bethesda, Md. 20814-3996 (301) 530-7145 Fax: (301) 571-1824 Gordon G. Hammes, president Charles Hancock, executive officer Biophysical Society 9650 Rockville Pike Room 0512 Bethesda, Md. 20814 (301) 530-7114 Fax: (301) 530-7133 E-mail: bj@biophysics.faseb.org Ralph G. Yaunt, president Emily M. Gray, executive director Protein Society 9650 Rockville PikeRoom B109 Bethesda, Md. 20814 (301) 530-7026 (800) 99-AMINO, Ext. 7026 Fax: (301) 530-7049 E-mail: pro@ns1.faseb.org Joseph Villafranka, president The following new journals publish structural biology research: Structure Editors: Wayne A. Hendrickson and Carl-Ivar Branden Main office: 34-42 Cleveland St. London, U.K. W1P 5FB Phone: (44) (71) 580 8377 Fax: (44) (71) 580 8428 E-mail: structure@cursci.co.uk U.S. editorial office: 251 Hugo St. San Francisco, Calif. 94122 (415) 566-4880 Fax: (415) 566-4594 U.S. managing editor: Rebecca Ward Nature Structural Biology Editor: Guy Riddihough Editorial office: 1234 National Press Building Washington, D.C. 20045 (202) 626-2518 Fax: (202) 626-2528 E-mail: nsb@linneus.naturedc.com Structural biologists have always considered their work--the study of the three-dimensional configurations of biological macromolecules such as proteins and nucleic acids-- profoundly important because it leads to understanding the relationships between form and function of subcellular components. But with rapid advances being made in the field, these scientists are coming to realize that structural studies hold the key to answering many larger questions in both basic and applied biological research. In the realm of basic investigations, structural biologists probe into problems that apply to both the plant and animal kingdoms. Guy Riddihough, editor of the fledgling journal Nature Structural Biology (Macmillan Magazines Ltd., London, England), points to such fundamental processes as photosynthesis and energy transformation in muscles as examples of biological reactions whose mechanisms are not fully understood because of inadequate information about the structures of the proteins involved. Other areas of basic research in which investigators are attempting to describe protein activity via their molecular structures include: antigen-antibody recognition, signal transduction (the transfer of messages across cell membranes), and the activation of cellular events such as RNA transcription and DNA replication. The wide reach of structural biology is also seen in industry, scientists say, because it is the basis for designing drugs and engineering various proteins such as vaccines, antibodies, and enzymes. As Riddihough puts it, when designing a drug against a particular virus, knowing the structure of the virus is important so that "we know what to inhibit." One of the most intriguing puzzles in fundamental biological research is elucidating the structural basis of energy transformation, say many scientists. Examples of such reactions are the conversion of light to chemical energy in the case of photosynthesis, and of chemical energy to motive power in muscles. Photosynthesis involves the capture of photons--discrete packages of light energy--by plant cells. This energy is used to split water molecules, ultimately producing food for the plant in the form of sugar and oxygen. "Photosynthesis is the single most important reaction on planet Earth--all life is dependent on it," says Kenneth Miller a researcher at Brown University, in Providence, R.I. "Even a 1 percent increase in efficiency of the process would have tremendous implications for the productivity of the land," adds Riddihough. While the first three-dimensional structure of a protein was described in the early 1950s on the basis of X-ray crystallography, the structure of the photosynthetic complex--the part of a plant's cell that captures photons-- proved more elusive. The main reason for this, say scientists, is that the photosynthetic apparatus is a complicated mixture of membrane-bound proteins intricately linked with light-sensitive pigment molecules called chlorophylls. "The standard `rap' was that membrane proteins could not be crystallized because of their hydrophobic nature," says Miller. But, notes Johann Deisenhofer, an investigator at the Howard Hughes Medical Institute Research Laboratories at the University of Texas Southwestern Medical Center in Dallas, his former colleague, crystallographer Hartmut Michel, "believed that a membrane protein [could] also be crystallized." Using a combination of detergents to solubilize the membrane proteins without distorting its conformation, Deisenhofer, Michel, and Robert Huber--working at the Max Planck Institute for Biochemistry in Martinsreid, Germany-- crystallized and solved the structure of the photosynthetic apparatus of the cyanobacterium Rhodopseudomonas viridis (H. Michel, Journal of Molecular Biology, 158:567-72, 1982). For this achievement, they received the 1988 Nobel Prize in chemistry. "Suddenly, in one glance, the field was advanced by a decade," says Miller. "We could see the bacteriochlorophyll pigment sitting in the heart of the reaction center." The reaction center is the location in the photosynthetic complex where photons are absorbed, and the resulting energy is used to split water molecules. But the photosynthesis story is still incomplete, researchers point out, with the light-harvesting complex in higher plants--called photosystem II--still defying all attempts at complete characterization. This leaves researchers with many questions--answers to which they hope to find as more structural details about the system become evident. For instance, Miller says that there is "a real prize" waiting for researchers in discovering the details of the water-splitting site of the photosynthetic membrane. A second trophy will come with an understanding of the conversion of a molecule called adenosine diphosphate (ADP) to its high-energy triphosphate form (ATP), which happens in response to the proton gradient generated when a water molecule is split during photosynthesis. Understanding the mechanisms of energy transfer involving ATP is also a target for those delving into the structural biology of the muscle proteins actin and myosin, according to Ivan Rayment, a scientist at the Institute for Enzyme Research in Madison, Wis. Myosin "is a funny-shaped molecule with two heads attached to a very long tail," says Rayment, who has been investigating its three-dimensional configuration. The structural details of myosin, he notes, made it finally possible to postulate how the molecule works as a motor to generate motion from ATP's chemical energy (I. Rayment, H.M. Holden, Trends in Biochemical Sciences, 19:129-34, 1994). The structural approach to understanding how molecules work has been of great practical importance to the pharmaceutical industry, say scientists, pointing to the many firms with large research groups of protein crystallographers. A dozen leading drug companies--including Abbott Laboratories, Abbott Park, Ill.; New York City-based Bristol-Myers Squibb Co.; Glaxo Inc. of Research Triangle Park, N.C.; Philadelphia-based SmithKline Beecham; and Procter & Gamble Co. in Cincinnati--have formed a consortium called the Industrial Macromolecular Crystallographic Association (IMCA) to share costs on building a common structural biology facility. IMCA will construct a $12 million experimental station, with a beam line off the Advanced Photon Source (APS), a U.S. Department of Energy-funded synchrotron-type X-ray source at Argonne National Laboratory in Illinois. APS will supply highly intense and focused X-rays that IMCA scientists will use in their various research projects. "We will share the costs of the facility, but each company will conduct its own research," says Cele Abad-Zapatero, a protein crystallographer at Abbott Laboratories and a member of IMCA's committee to supervise the building of the beam line. For his company, Abad-Zapatero adds, "it will be like having a synchrotron in our backyard" because of the proximity of APS and Abbott's headquarters. Since the X-rays from APS are several times more brilliant than those produced in-house by any of the companies, researchers at the new facility will be able to conduct their experiments far more efficiently than before, says Steven Jordan, a scientist representing Glaxo Inc. in IMCA. Jordan will use the X-rays to facilitate his research on anti-cancer drugs, which he is designing to inhibit a class of enzymes called tyrosine kinases. "An aberrant form of this enzyme is seen, associated with several cancers," he says. In addition to designing drugs that inhibit the protein components of infectious agents, industrial researchers are looking into modifying the structures of proteins themselves. For instance, Abad-Zapatero has worked on improving the characteristics of the enzyme alkaline phosphatase, which is used by Abbott Labs in various diagnostic kits and assays. "Originally we used [alkaline phosphatase] from calf intestines, but this was a very labile enzyme," he says. A cheaper, stabler form of the enzyme was discovered in the bacterium Escherichia coli. But Zapatero explains that the activity of the enzyme was too low to be substituted for the calf enzyme in the assay kits. Through a combination of mutagenic and X-ray crystallographic techniques, the researchers were able to pinpoint the location of the enzymatic activity to engineer improved forms of the bacterial enzyme for use in their kits. The structure of the mutant enzyme is described by Abad- Zapatero and his colleagues in a paper in the journal Protein Engineering (L. Chen et al., 5:605-10, 1992). As the scientific community is flooded with a torrent of structural data, researchers are looking ahead to future challenges and discoveries that the study of proteins will bring. "One of the biggest challenges is to use the structural information more efficiently," says Jordan. "We need to understand the dynamics of structure properly." For instance, he says, scientists still can't predict exactly how a drug is going to behave when it comes in contact with a protein. "Not all structures generate a great `aha' of instant insight into biological activity," wrote Wayne Hendrickson and Carl Ivan-Branden, the editors of a new journal, Structure, (Current Biology Ltd., London) in the first editionUs opening essay (Introductory issue, pages i-ii, 1993). But recognition of the biological significance of a new structure is often inspirational, they add. "The implications [of structural biology] are profound in the extreme," says Guy Riddihough. He speculates that biological structures could yield meaningful insights into some of the most fundamental puzzles that scientists are attempting to solve: "Questions about the origin of life could be answered."

Molecular Structures Provide Insights Into Larger Questions In Biology

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