318 GROUP I AND II METALS IN BIOLOGICAL SYSTEMS: GROUP II
helices D and E of the central linker. As can be seen in Table 6.9 , a basic
residue (arg, lys, his) occurs at this position on the peptide chain for all
calmodulin - binding peptides listed, making this a universally important residue
for this group of peptides. Mutagenesis studies on the interaction of CaM with
smMLCK have shown the critical importance of peptide residues trp4 (1),
arg16 (13), and leu17 (14) for successful CaM – smMLCK binding. The studies
also indicate that these residues or close analogs are conserved in other target
enzymes (see Table 6.9 ). Additionally, it has been observed that mutation of
three residues in CaM ’ s N - terminal domain converts calmodulin from agonist
(assistor of target enzyme activity) to potent antagonist (binder that sup-
presses target enzyme activity). This observation leads the reference 86a
authors to propose that the peptide N - terminal domain fi rst acts with the
peptide ’ s C - terminal end, followed by arg16 (13) interaction with the central
linker loop – helix domain. Finally, the peptide ’ s C - terminal end would be
pulled from its place in the larger target enzyme to interact with CaM ’ s N -
terminal domain completing the enzyme activation process.
In late 1993, the Quiocho group reported the 2.00 - Å resolution X - ray crys-
tallographic structure of a Ca 2+ - saturated CaM with the CaM - binding domain
peptide of bovine brain CaM - dependent protein kinaseII α (CaMKII, PDB:
1CDM).86b The authors compared the CDM structure to that of Ca 2+ - staurated
CaM (PDB: 1CLL, reference 72 ) and to that of Ca 2+ - staurated CaM com-
plexed with smMLCK (PDB: 1CDL discussed in previous paragraphs). Resi-
dues 293 – 310 of the CaMKII peptide make approximately 135 contacts of
≤ 4 Å with the Ca 2+ - saturated CaM in a structure very similar to that of
PDB: 1CDL discussed above (with approximately 185 contacts). However, in
the PDB: 1CDM structure, the CaM central linker loop residues 74 – 83 are
Figure 6.27 Three different calmodulin - binding peptides in complexes with calmodu-
lin (PDB: 2BBM, 1CDL, and 1CDM). Visualized using CambridgeSoft Chem3D Ultra
10.0 with notations in ChemDraw Ultra 10.0. (Printed with permission of Cambridge-
Soft Corporation.)
PDB: 2BBM PDB: 1CDL PDB: 1CDMala1lys148thr5thr146leu4thr146