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Manipulating Protein–Protein Interactions in Nonribosomal Peptide Synthetase Type II Peptidyl Carrier Proteins
In an effort to elucidate
and engineer interactions in type II
nonribosomal peptide synthetases, we analyzed biomolecular recognition
between the essential peptidyl carrier proteins and adenylation domains
using nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics,
and mutational studies. Three peptidyl carrier proteins, PigG, PltL,
and RedO, in addition to their cognate adenylation domains, PigI,
PltF, and RedM, were investigated for their cross-species activity.
Of the three peptidyl carrier proteins, only PigG showed substantial
cross-pathway activity. Characterization of the novel NMR solution
structure of holo-PigG and molecular dynamics simulations of holo-PltL
and holo-PigG revealed differences in structures and dynamics of these
carrier proteins. NMR titration experiments revealed perturbations
of the chemical shifts of the loop 1 residues of these peptidyl carrier
proteins upon their interaction with the adenylation domain. These
experiments revealed a key region for the protein–protein interaction.
Mutational studies supported the role of loop 1 in molecular recognition,
as mutations to this region of the peptidyl carrier proteins significantly
modulated their activities