Principles of Protein Structure - H. Schultz 1982

Protein-Ligand Interactions
Ligand-Binding Sites of Immunoglobulins
Immunoglobulin-Ligand Systems as Models for Other Protein-Ligand Interactions

Our understanding of Protein–Ligand interactions remains so limited that X-Ray Diffraction Analysis is still required in each specific case to obtain reliable data [623]. This approach cannot be applied to all Proteins, if only because many of the most fascinating ones, such as Membrane Proteins, resist crystallization. Therefore, it is crucial to derive general rules of ligand binding based on already available data.

Immunoglobulin–ligand complexes are best suited for this purpose because, as noted above, a fairly systematic approach to the problem has been developed for them.

Immunoglobulin–ligand complexes share similarities with enzyme–ligand complexes. There are clear parallels between the binding properties of IMMUNOGLOBULINS and Enzymes [85, 624, 625]:

a) As indicated by rate constants (up to 10⁸ М^-1∙ с^-1), the binding step is frequently a diffusion-controlled reaction.

б) The bound ligand exhibits low rotational freedom; it is held firmly and specifically by noncovalent interactions. Standard free energies of binding range from -6 to -15 kcal/mol, which corresponds to ligand–enzyme dissociation constants from K = 10^-4 М to K = 10^-10 М.

в) Ligand binding by immunoglobulins can apparently be described by the lock-and-key model [44]. While this also holds true for many enzyme–ligand interactions, it does not apply to enzymes that undergo significant conformational changes upon ligand binding (induced fit) [626].

The architecture of immunoglobulin can serve as a basis for the in vitro synthesis of Peptides with tailored binding properties.

For theoretical and practical research, the in vitro synthesis of a polypeptide chain with a defined Specificity and affinity for a given compound could prove extremely valuable. One potential approach may start with a natural or synthetic V_L/V_H domain lacking hypervariable loops as a structural scaffold. By incorporating suitable sequences in place of the hypervariable segments, a specific binding site for the target ligand can then be engineered without disrupting the folding process or the Stability of the scaffold [498]. The example of a Cu^z+–Zn²⁺-containing superoxide dismutase [286] can be viewed as a natural precedent for this peptide engineering method. In this case, the coordination geometry of the metal atoms in the active sites shares much in common with the corresponding fragments of crystalline copper-imidazole and zinc-imidazole complexes [661]. Thus, both KEY FEATURES OF this enzyme—the immunoglobulin Structure and the metal complex—can be replicated by organic chemists.