Terazosin Activates or Inhibits Human Phosphoglycerate Kinase 1 on a Dose-Dependent Basis: Mechanistic and Structural Insights by NMR.
- 1Institute for Molecular Physical Science, Vladimir Prelog Weg 2, 8093 Zürich, Switzerland.
- 2Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, A-1090 Vienna, Austria.
- 3NexMR AG, Wiesenstrasse 10A, 8952 Schlieren, Switzerland.
Abstract
Phosphoglycerate kinase 1 (PGK1) is a key metabolic enzyme responsible for ATP production, and its dysregulation is linked to the Warburg effect in cancer and to neurodegenerative diseases such as Parkinson's. Recent studies indicate that terazosin, an FDA-approved drug, enhances PGK1-mediated ATP production. However, X-ray crystallography indicates that terazosin binds at a site that partially overlaps the nucleotide-binding site, thereby inhibiting PGK1. In this study, we employed solution-state nuclear magnetic resonance (NMR) chemical shift titrations to confirm that terazosin binds at a site that partially overlaps the nucleotide-binding pocket of PGK1, stabilizing the enzyme in its open conformation, which is accessible to substrates and products. This binding shifts the equilibrium toward the open state, enhancing product release at low concentrations while blocking substrate binding at higher concentrations. These findings are strengthened by the 3D NMR2 structure determination of the PGK1-terazosin complex, using selective unlabeling combined with subsequent partial amino acid assignments, which validates the available X-ray structure.
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BibTeX
@article{butikofer2026terazosin,
title = {{Terazosin Activates or Inhibits Human Phosphoglycerate Kinase 1 on a Dose-Dependent Basis: Mechanistic and Structural Insights by NMR.}},
author = {Matthias Bütikofer and Felix Torres and Dhiman Ghosh and Nils Lorz and Roland Riek and Julien Orts},
journal = {JACS Au},
year = {2026},
month = sep,
doi = {10.1021/jacsau.6c00823},
url = {https://europepmc.org/article/MED/42953203},
note = {CC BY},
}
RIS
TY - JOUR
TI - Terazosin Activates or Inhibits Human Phosphoglycerate Kinase 1 on a Dose-Dependent Basis: Mechanistic and Structural Insights by NMR.
AU - Matthias Bütikofer
AU - Felix Torres
AU - Dhiman Ghosh
AU - Nils Lorz
AU - Roland Riek
AU - Julien Orts
PY - 2026
DA - 2026/09/24
JO - JACS Au
DO - 10.1021/jacsau.6c00823
UR - https://europepmc.org/article/MED/42953203
AB - Phosphoglycerate kinase 1 (PGK1) is a key metabolic enzyme responsible for ATP production, and its dysregulation is linked to the Warburg effect in cancer and to neurodegenerative diseases such as Parkinson's. Recent studies indicate that terazosin, an FDA-approved drug, enhances PGK1-mediated ATP production. However, X-ray crystallography indicates that terazosin binds at a site that partially overlaps the nucleotide-binding site, thereby inhibiting PGK1. In this study, we employed solution-state nuclear magnetic resonance (NMR) chemical shift titrations to confirm that terazosin binds at a site that partially overlaps the nucleotide-binding pocket of PGK1, stabilizing the enzyme in its open conformation, which is accessible to substrates and products. This binding shifts the equilibrium toward the open state, enhancing product release at low concentrations while blocking substrate binding at higher concentrations. These findings are strengthened by the 3D NMR2 structure determination of the PGK1-terazosin complex, using selective unlabeling combined with subsequent partial amino acid assignments, which validates the available X-ray structure.
SN - 2691-3704
ER -