TY - JOUR
T1 - Global protein dynamics as communication sensors in peptide synthetase domains
AU - Mishra, Subrata H.
AU - Kancherla, Aswani K.
AU - Marincin, Kenneth A.
AU - Bouvignies, Guillaume
AU - Nerli, Santrupti
AU - Sgourakis, Nikolaos
AU - Dowling, Daniel P.
AU - Frueh, Dominique P.
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved
PY - 2022/7
Y1 - 2022/7
N2 - Biological activity is governed by the timely redistribution of molecular interactions, and static structural snapshots often appear insufficient to provide the molecular determinants that choreograph communication. This conundrum applies to multidomain enzymatic systems called nonribosomal peptide synthetases (NRPSs), which assemble simple substrates into complex metabolites, where a dynamic domain organization challenges rational design to produce new pharmaceuticals. Using a nuclear magnetic resonance (NMR) atomic-level readout of biochemical transformations, we demonstrate that global structural fluctuations help promote substrate-dependent communication and allosteric responses, and impeding these global dynamics by a point-site mutation hampers allostery and molecular recognition. Our results establish global structural dynamics as sensors of molecular events that can remodel domain interactions, and they provide new perspectives on mechanisms of allostery, protein communication, and NRPS synthesis.
AB - Biological activity is governed by the timely redistribution of molecular interactions, and static structural snapshots often appear insufficient to provide the molecular determinants that choreograph communication. This conundrum applies to multidomain enzymatic systems called nonribosomal peptide synthetases (NRPSs), which assemble simple substrates into complex metabolites, where a dynamic domain organization challenges rational design to produce new pharmaceuticals. Using a nuclear magnetic resonance (NMR) atomic-level readout of biochemical transformations, we demonstrate that global structural fluctuations help promote substrate-dependent communication and allosteric responses, and impeding these global dynamics by a point-site mutation hampers allostery and molecular recognition. Our results establish global structural dynamics as sensors of molecular events that can remodel domain interactions, and they provide new perspectives on mechanisms of allostery, protein communication, and NRPS synthesis.
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U2 - 10.1126/sciadv.abn6549
DO - 10.1126/sciadv.abn6549
M3 - Article
C2 - 35857508
AN - SCOPUS:85134639235
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 28
M1 - eabn6549
ER -