Antigen-Antibody Binding Introductory article zumi Kumagai,Tohoku University,Sendai.Jopon Artice Contents Kouhei Tsumoto,Tohoku University,Sendai,Japan en- igenic Epitope (antigens).The bindina be Antigen-bindir resulting from various structural and energetic aspects. dy Affinity and Introduction immunoglobulin fold(Figure 2).The N-terminal domain of prevention and resolution of infection by foreign invaders the remaining domains have )while the latter is the constantregion (Cr such as viruses.Antibodies are a family of variable In addition,a comparison of V region sequences shows inte cions is their high sp that variability is not uniformly distributed but concen- ed into three areas called the hypervariable article,the structural and energetic aspects of antigen- antibody binding are described,focusing in particular on have demonstrated that the domain hoarnanibcdyecicalyrecognmizesiscognateantigen structure of the antibody molecule is a B barrel consisting of nine antiparallel B strands V regions)and seven an antigen (epitope)and an antigen-binding site in an antibody(paratope)is termed affinity.Each antibody unit has at least two six polypeptide segments,three from light variable antigen-b ling sites,and is domains and three from heavy variable domains.These tibody with its n which egments show vana lty in se is related to both the affinity of the reaction and the ence as be for the diversity found in the binding of the different antibodies.These six hypervariable segments are often referred to as the complementarity-determining sthat a more Antigen-Antibody Binding immunoglobulin fold that results in the CDRs being Antibody structure rame V domains and maintaining the integrity of the binding identical heavy chains linked together by disulfide bonds fer in amnt tial s in th sOu6cean work regions).This characteristic structure has led to chains.There are two different isotypes of light chains several approaches to the artificial design of novel and K).Immunoglobulin G(IgG)is the major type of antibodies by grafting new CDRs onto existing antibodies (Figure 3) (Figure 1). h scquences from various immunoglobulin molccules.This Canonical structure of CDRs shows that immunoglobulins are composed of various The antigen-binding specificity of an antibody is defined by ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group/www.els.net Antigen–Antibody Binding Izumi Kumagai, Tohoku University, Sendai, Japan Kouhei Tsumoto, Tohoku University, Sendai, Japan Antibodies are a family of glycoproteins that bind specifically to foreign molecules (antigens). The binding between antibodies and antigens has high specificity and affinity resulting from various structural and energetic aspects. Introduction Antibodies (immunoglobulins) are produced by the immune system of vertebrates and are essential for the prevention and resolution of infection by foreign invaders such as viruses. Antibodies are a family of variable glycoproteins that bind specifically to foreign molecules (antigens). The most striking feature of antigen–antibody interactions is their high specificity and affinity. In this article, the structural and energetic aspects of antigen– antibody binding are described, focusing in particular on howan antibody specifically recognizes its cognate antigen and binds to it tightly. A binding strength between an antigenic determinant in an antigen (epitope) and an antigen-binding site in an antibody (paratope) is termed affinity. Each antibody unit has at least two antigen-binding sites, and is therefore bivalent, or multivalent, to its antigen. The functional combining strength of an antibody with its antigen, which is related to both the affinity of the reaction and the valencies of the antibody, is termed avidity. The signifi- cance of avidity to antigen–antibody binding is also described. Antigen–Antibody Binding Antibody structure The basic structure of an antibody (immunoglobulin) molecule comprises two identical light chains and two identical heavy chains linked together by disulfide bonds. There are five classes of immunoglobulins (IgG, IgA, IgM, IgD and IgE), which differ in amino acid sequence and number of domains in the constant regions of the heavy chains. There are two different isotypes of light chains (l and k). Immunoglobulin G (IgG) is the major type of immunoglobulin in normal serum and the most extensively investigated (Figure 1). The remarkable feature of the antibody molecule is revealed by comparison of amino acid sequences from various immunoglobulin molecules. This shows that immunoglobulins are composed of various copies of a folding unit of about 100 amino acids, each of which forms an independent similar structure called the immunoglobulin fold (Figure 2). The N-terminal domain of each polypeptide (heavy and light chains) is highly variable, while the remaining domains have constant sequences. The former domain is called the variable region (V region), while the latter is the constant region (C region). In addition, a comparison of V region sequences shows that variability is not uniformly distributed but concen￾trated into three areas called the hypervariable regions. Investigations into the structures of various antigen– antibody complexes have demonstrated that the domain structure of the antibody molecule is a b barrel consisting of nine antiparallel b strands (V regions) and seven C regions, and that the hypervariable regions are clustered at the end of the variable domain arms (Figure 3). The antigen￾combining site of antibodies is formed almost entirely by six polypeptide segments, three from light variable domains and three from heavy variable domains. These segments showvariability in sequence as well as in number of residues, and it is this variability that provides the basis for the diversity found in the binding characteristics of the different antibodies. These six hypervariable segments are often referred to as the complementarity-determining regions or CDRs. It was realized that a more constant sequence of residues outside of the CDRs was required to maintain the essential immunoglobulin fold that results in the CDRs being brought into three-dimensional proximity. These residues are referred to as the framework regions. The framework residues do not usually form bonds with the antigen. However, they are essential for producing the folding of the V domains and maintaining the integrity of the binding site. Thus, the antibody-binding sites are formed by six segments of variable structure (CDRs) supported by a scaffolding of essentially invariant architecture (frame￾work regions). This characteristic structure has led to several approaches to the artificial design of novel antibodies by grafting newCDRs onto existing antibodies (Figure 3). Canonical structure of CDRs The antigen-binding specificity of an antibody is defined by the physical and chemical properties of its CDR surface. These in turn are determined by the conformation of the Article Contents Introductory article . Introduction . Antigen–Antibody Binding . Antigenic Epitope . Forces Involved in Antigen-binding . Affinity and Avidity . Biological Significance of Antibody Affinity and Multivalency ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 1