STRUCTURAL MODELING OF THE PRO-OCYTOCIN-NEUROPHYSIN PRECURSOR

The hormonal precursor pro-ocytocin-neurophysin is activated by select ive cleavage at Arg12-Ala13, producing mature ocytocin and neurophysin , To understand the cleavage mechanism better, and in particular the r ecognition of the cleavage site, it is necessary to characterize the t hree-dimensional structure of the precursor molecule. Here we combine a variety of experimental data with molecular modeling and dynamics ca lculations to derive possible precursor conformations, In the models o btained, the N-terminus of the precursor, corresponding to the ocytoci n segment, is hydrogen bonded in a pocket of the neurophysin moiety in a similar manner to a crystallographically obtained non-covalent comp lex between the two molecules. The calculations suggest that although the ocytocin segment is relatively flexible, it adopts a stable, broad loop structure in the vicinity of the cleavage region, which may cons titute the structural element recognized by the cleaving enzyme, The c alculations also suggest a possible widening of the distance between t he two neurophysin domains in the precursor relative to that in the no n-covalent neurophysin-ocytocin complex.