Ligand structural complementarity

Figure 1.4 Left panel Space filing model of the structure of bacterial dihydrofolate reductase with methotrexate bound to the active site. Right panel Close-up view of the active site, illustrating the structural complementarity between the ligand (methotrexate) and the binding pocket. See color insert. Source Courtesy of Nesya Nevins.

Receptors exhibit structural complementarity with their ligand in the same way that enzymes are complementary to their substrate. Often the actual binding of the hormone to its receptor involved just a small portion of both molecules. The peptide ACTH secreted by the pituitary gland contains 39 amino acids, but only about 12 of these near the N-terminal are required to engage the receptor. Furthermore, and as noted in Section 4.4.1, LH, FSH, TSH and hCG all share a common a subunit and their receptors recognize only the [3 unit. 

Structural Complementarity and Energy Balance in Ligand/Receptor Binding... 

In any case, an absolute prerequisite for specific binding is the structural complementarity of ligand and receptor at the recognition site. Any lack of complementarity, caused by unfavorable van der Waals contacts between sterically interfering groups, will interfere with specific binding to the active site. Structural and conformational aspects of the mutual binding process are discussed in more detail in Section 13.2. 

Desjarlais R L, R P Sheridan, G L Seibel, J S Dixon, ID Kuntz and R Venkataraghavan 1988. Using Shap Complementarity as an Initial Screen in Designing Ligands for a Receptor Binding Site of Know Three-Dimensional Structure. Journal of Medicinal Chemistry 31 722-729. 

Once the protein interaction pattern is translated from Cartesian coordinates into distances from the reactive center of the enzyme and the structure of the ligand has been described with similar fingerprints, both sets of descriptors can be compared [25]. The hydrophobic complementarity, the complementarity of charges and H-bonds for the protein and the substrates are all computed using Carbo similarity indices [26]. The prediction of the site of metabolism (either in CYP or in UGT) is based on the hypothesis that the distance between the reactive center on the protein (iron atom in the heme group or the phosphorous atom in UDP) and the interaction points in the protein cavity (GRID-MIF) should correlate to the distance between the reactive center of the molecule (i.e. positions of hydrogen atoms and heteroatoms) and the position of the different atom types in the molecule [27]. 

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