TY - JOUR

T1 - Conserved conformational dynamics determine enzyme activity

AU - Torgeson, Kristiane R.

AU - Clarkson, Michael W.

AU - Granata, Daniele

AU - Lindorff-Larsen, Kresten

AU - Page, Rebecca

AU - Peti, Wolfgang

N1 - Publisher Copyright: © 2022 American Association for the Advancement of Science. All rights reserved.

PY - 2022

Y1 - 2022

N2 - Homologous enzymes often exhibit different catalytic rates despite a fully conserved active site. The canonical view is that an enzyme sequence defines its structure and function and, more recently, that intrinsic protein dynamics at different time scales enable and/or promote catalytic activity. Here, we show that, using the protein tyrosine phosphatase PTP1B, residues surrounding the PTP1B active site promote dynamically coordinated chemistry necessary for PTP1B function. However, residues distant to the active site also undergo distinct intermediate time scale dynamics and these dynamics are correlated with its catalytic activity and thus allow for different catalytic rates in this enzyme family. We identify these previously undetected motions using coevolutionary coupling analysis and nuclear magnetic resonance spectroscopy. Our findings strongly indicate that conserved dynamics drives the enzymatic activity of the PTP family. Characterization of these conserved dynamics allows for the identification of novel regulatory elements (therapeutic binding pockets) that can be leveraged for the control of enzymes.

AB - Homologous enzymes often exhibit different catalytic rates despite a fully conserved active site. The canonical view is that an enzyme sequence defines its structure and function and, more recently, that intrinsic protein dynamics at different time scales enable and/or promote catalytic activity. Here, we show that, using the protein tyrosine phosphatase PTP1B, residues surrounding the PTP1B active site promote dynamically coordinated chemistry necessary for PTP1B function. However, residues distant to the active site also undergo distinct intermediate time scale dynamics and these dynamics are correlated with its catalytic activity and thus allow for different catalytic rates in this enzyme family. We identify these previously undetected motions using coevolutionary coupling analysis and nuclear magnetic resonance spectroscopy. Our findings strongly indicate that conserved dynamics drives the enzymatic activity of the PTP family. Characterization of these conserved dynamics allows for the identification of novel regulatory elements (therapeutic binding pockets) that can be leveraged for the control of enzymes.

U2 - 10.1126/sciadv.abo5546

DO - 10.1126/sciadv.abo5546

M3 - Journal article

C2 - 35921420

AN - SCOPUS:85135470924

VL - 8

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 31

M1 - eabo5546

ER -