Affiliation:
1. Beckman Institute, California Institute of Technology, Pasadena, CA 91125
Abstract
The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT
10
), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand. Two optimized computational models of the copper(II)-peptide complexes were derived: One corresponding to pH 6.5 and the other describing the complex at pH 7.5 to 8.5. Simulated EPR spectra based on the calculated model structures are in good agreement with experimental spectra.
Funder
HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases
HHS | NIH | National Heart, Lung, and Blood Institute
Arnold and Mabel Beckman Foundation
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Publisher
Proceedings of the National Academy of Sciences