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Global protein dynamics as communication sensors in peptide synthetase domains.
Mishra, Subrata H; Kancherla, Aswani K; Marincin, Kenneth A; Bouvignies, Guillaume; Nerli, Santrupti; Sgourakis, Nikolaos; Dowling, Daniel P; Frueh, Dominique P.
Afiliação
  • Mishra SH; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Kancherla AK; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Marincin KA; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Bouvignies G; Laboratoire des Biomolécules (LBM), Département de Chimie, École normale supérieure, PSL University, Sorbonne Université, CNRS, Paris, France.
  • Nerli S; Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
  • Sgourakis N; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Dowling DP; Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA.
  • Frueh DP; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sci Adv ; 8(28): eabn6549, 2022 Jul 15.
Article em En | MEDLINE | ID: mdl-35857508
ABSTRACT
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.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2022 Tipo de documento: Article