Disulfide bond plasticity in epidermal growth factor

Epidermal growth factor (EGF) has a (1-3,2-4,5-6) disulfide-bonding pattern . This pattern is found in nearly all EGF-like domains, despite wide variat ion in sequences. Biological data from EGF and at least one EGF-Like domain show that disulfide bond isomers have significant bioactivity and suggests that the EGF fold can accommodate alternate disulfide-bonding patterns. Th e disulfide bonds in murine EGF were altered to seven different patterns an d structures mere calculated incorporating all the restraints from the high est resolution restraint set available (Tejero et al., 1996). Results showe d that besides the native (1-3,2-4,5-6), two other disulfide-bonding patter ns: (1-2,3-4,5-6) and (1-3,2-5,4-6) satisfied the restraints as well as the native. The results for these two patterns were indistinguishable from the native on the basis of distance and dihedral violations, XPLOR energies, P rocheck statistics, and RMSDs of the final set of structures. Two other dis ulfide bond patterns, (1-2,3-5, 4-6) and (1-4,2-3,5-6) were able to satisfy all the distance restraints but had one or more cysteine dihedral violatio ns. For all seven isomers, the final calculated structures were highly simi lar to EGF with all-atom RMSD's in the 1.5-2 Angstrom range. These results suggest that the EGF backbone fold has the unique property of accommodating several different disulfide-bonding patterns.(C) 2000 Wiley-Liss, Inc.