Chemistry and Immunology - American Chemical Society

expanded enormously with the development of mon- oclonal antibodies and genetic ... mechanisms that probably go beyond simple structural complementari...
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VOLUME 26 NUMBER 8

AUGUST 1993 Registered in US.Patent and Trademark Office; Copyright 1993 by the American Chemical Society

Editorial Chemistry and Immunology: A Powerful Combination Tools and concepts developed in each of these fields are being carried across their traditional boundaries to solve important problems in both. Chemistry offers rigorous assessment of molecular structures and mechanisms of molecular interactions, properties that ultimately provide the basis of all immune responses, however complex. The most important gift of immunology to chemistry currently is the programmable binding site, best known from its form in immunoglobulin (antibody) binding to a ligand (antigen). These high-specificity sites, created naturally within the immunoglobulin protein to eliminate foreign invaders, can be induced to recognize a vast array of chemical structures. This provides for chemists the opportunity to harness nature’s synthetic skills, and also to explore the noncovalent interactions of folded polypeptides that lead to exquisite three-dimensional complementarity with a ligand. Exploitation of antibodies for applications in research, medicine, and other areas has expanded enormously with the development of monoclonal antibodies and genetic engineering techniques. This issue of Accounts, organized by guest editors Peter Schultz and Richard Lerner, presents a selection of success stories and ongoing progress reports from this alliance between chemistry and immunology. A prime example is provided by catalytic antibodies developed by chemists to produce enzyme-like binding sites specificfor transition-state analogues that catalyze the conversion of substrate to product. As described by Schultz and Lerner, there has been increasingly sophisticated use of antibody binding energy to control the outcome of chemical reactions, even to catalyze “disfavored”chemical transformations that are difficult if not impossible to achieve by existing chemical methods. Stewart et al. focus on the catalytic antibody mechanisms that probably go beyond simple structural complementarity. A rich chemistry can occur in the confined space walled by a protein; mechanistic schemes elucidated for enzyme active sites can also be utilized

for catalytic antibodies that are more readily engineered.

As described by Burton, the methods of modern molecular biology and genetic engineering have revolutionized the capability to design antibody binding sites and to enhance their production and selection, including establishment in bacteria of the genes for the light and heavy chains of all antibodies elicited against a particular antigen. Expression of the resulting combinatorial library of antibodies allows selection for a variety of specificities, further expanded by mutagenesis and other manipulations. Schreiber et al. demonstrate the power of natural products chemistry to address complex problems in cell biology, such as the cell cycle and receptor-mediated signal transduction occurring in T cells. The molecular interactions of the immunosuppressant drugs cyclosporin A, FK506, and rapamycin illuminate the natural cellular pathways. Davies and Chacko review the detailed picture of immunoglobulin structure that has been provided by a long history of X-ray crystallographic studies of immunoglobulin G (IgG). These polypeptides are folded into a characteristic domain structure that has emerged as a recurring structural motif throughout the immune system, as illustrated in the cover figure. Paired domains are arranged in a tripartite structure containing an Fc segment, which binds to other effector proteins, and two Fab segments which contain the antigen binding sites at the distal ends, with polypeptide chain folding providing specificity and affinity. Baird et al. use fluorescence to investigate the IgE system, a model for many types of immunoreceptors that are cross-linked by antigen to cause cellular activation. Fluorescence resonance-energy transfer indicates IgE conformation, orientation, and flexibility when IgE is bound via its Fc segment to its cell surface receptor, and, unlike X-ray crystallography, can be carried out in heterogeneous mixtures containing cells to allow direct correlation with biological activity.

0001-4842/93/0126-0389$04.00/00 1993 American Chemical Society

Editorial

390 Ace. Chem. Res., Vol. 26,No. 8, 1993 Cellular responses resulting from receptors on T cells binding to antigen-presenting cells play a central role in the immune system, with interdisciplinary efforts now uncovering some of the critical molecular features. Here the antigen is a peptide associated with a selfidentification protein known as the major histocompatibility complex (MHC; classes I and 11). Rock and Davis compare and contrast the protein composition of immunoglobulin and T cell receptors, with a framework to view similar structures having very different functions. New methodologies show the binding of T cell receptors to peptide-MHC ligands to be of low affinity, although of high specificity, implying unusual functional effects. Witt and McConnell describe the demanding immunological constraints placed on peptide interactions with MHC (class 11). A detailed investigationof the chemical kinetics developsinsightful kinetic models for their experimental data. Harrison considers the CD4 cell surface protein present on T cells that recognize class I1 MHC; CD4 not only plays a role in the recognition complex but also is the receptor

for the human immunodeficiency virus allowing its entry into these T cells and eventual devastation of the immune system. High-resolutionX-ray crystallography of soluble preparations confirms that CD4 is also a member of the immunoglobulin superfamily and indicates its functional roles. This issue of Accounts takes the reader from the intricacies of chemical reactions controlled systematically by immunologically-derived binding sites to the application of chemistry to elucidate complex immunological structures and cellular processes. The power of the combined efforts of chemistry and immunology promises a bright future, with expanding applications leading to major advances in both fields. Barbara A. Baird Associate Editor Fred W. McLafferty Editor

Cover Photo: Exquisite recognition by the immunoglobulin binding site is illustrated in this X-ray crystallographic structure of the HyHEL-10 antilysozymeFab segment (bottom parts) in association with (left) and separated from (right) its ligand. (Padlan, E. A.; Siverton, E. W.; Sheriff, S.; Cohen, G. H.; Smith-Gill, S. J.; Davies, D. R. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 5938-5942.)