Details
Originalsprache | Englisch |
---|---|
Seiten (von - bis) | 128-137.e5 |
Fachzeitschrift | STRUCTURE |
Jahrgang | 31 |
Ausgabenummer | 2 |
Frühes Online-Datum | 6 Jan. 2023 |
Publikationsstatus | Veröffentlicht - 2 Feb. 2023 |
Abstract
Non-structural protein 1 (Nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major virulence factor and thus an attractive drug target. The last 33 amino acids of Nsp1 have been shown to bind within the mRNA entry tunnel of the 40S ribosomal subunit, shutting off host gene expression. Here, we report the solution-state structure of full-length Nsp1, which features an α/β fold formed by a six-stranded, capped β-barrel-like globular domain (N-terminal domain [NTD]), flanked by short N-terminal and long C-terminal flexible tails. The NTD has been found to be critical for 40S-mediated viral mRNA recognition and promotion of viral gene expression. We find that in free Nsp1, the NTD mRNA-binding surface is occluded by interactions with the acidic C-terminal tail, suggesting a mechanism of activity regulation based on the interplay between the folded NTD and the disordered C-terminal region. These results are relevant for drug-design efforts targeting Nsp1.
ASJC Scopus Sachgebiete
- Biochemie, Genetik und Molekularbiologie (insg.)
- Strukturelle Biologie
- Biochemie, Genetik und Molekularbiologie (insg.)
- Molekularbiologie
Zitieren
- Standard
- Harvard
- Apa
- Vancouver
- BibTex
- RIS
in: STRUCTURE, Jahrgang 31, Nr. 2, 02.02.2023, S. 128-137.e5.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Structural insights into the activity regulation of full-length non-structural protein 1 from SARS-CoV-2
AU - Wang, Ying
AU - Kirkpatrick, John
AU - Lage, Susanne zur
AU - Carlomagno, Teresa
N1 - Funding Information: We thank Dr Andrea Graziadei (TU Berlin) for the kind gift of the Nsp1 expression plasmid and Prof. Dr. Harald Schwalbe (Goethe University Frankfurt, BMRZ) and Dr. Julia Weigand (Technical University Darmstadt) for the kind gift of the DNA template plasmids of the 5′ UTR region of the SARS-CoV-2. This work was funded by the Deutsche Forschungsgemeinschaft through grant CA294/16-1 to T.C. We thank Dr Andrea Graziadei (TU Berlin) for the kind gift of the Nsp1 expression plasmid and Prof. Dr. Harald Schwalbe (Goethe University Frankfurt, BMRZ) and Dr. Julia Weigand (Technical University Darmstadt) for the kind gift of the DNA template plasmids of the 5′ UTR region of the SARS-CoV-2. This work was funded by the Deutsche Forschungsgemeinschaft through grant CA294/16-1 to T.C. Y.W. and J.K. performed research, analyzed data, and wrote the manuscript; S.z.L. performed research; and T.C. designed and supervised the project, analyzed data, and wrote the manuscript. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
PY - 2023/2/2
Y1 - 2023/2/2
N2 - Non-structural protein 1 (Nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major virulence factor and thus an attractive drug target. The last 33 amino acids of Nsp1 have been shown to bind within the mRNA entry tunnel of the 40S ribosomal subunit, shutting off host gene expression. Here, we report the solution-state structure of full-length Nsp1, which features an α/β fold formed by a six-stranded, capped β-barrel-like globular domain (N-terminal domain [NTD]), flanked by short N-terminal and long C-terminal flexible tails. The NTD has been found to be critical for 40S-mediated viral mRNA recognition and promotion of viral gene expression. We find that in free Nsp1, the NTD mRNA-binding surface is occluded by interactions with the acidic C-terminal tail, suggesting a mechanism of activity regulation based on the interplay between the folded NTD and the disordered C-terminal region. These results are relevant for drug-design efforts targeting Nsp1.
AB - Non-structural protein 1 (Nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major virulence factor and thus an attractive drug target. The last 33 amino acids of Nsp1 have been shown to bind within the mRNA entry tunnel of the 40S ribosomal subunit, shutting off host gene expression. Here, we report the solution-state structure of full-length Nsp1, which features an α/β fold formed by a six-stranded, capped β-barrel-like globular domain (N-terminal domain [NTD]), flanked by short N-terminal and long C-terminal flexible tails. The NTD has been found to be critical for 40S-mediated viral mRNA recognition and promotion of viral gene expression. We find that in free Nsp1, the NTD mRNA-binding surface is occluded by interactions with the acidic C-terminal tail, suggesting a mechanism of activity regulation based on the interplay between the folded NTD and the disordered C-terminal region. These results are relevant for drug-design efforts targeting Nsp1.
KW - disordered protein domains
KW - drug targets
KW - NMR spectroscopy
KW - non-structural proteins
KW - Nsp1
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85147029540&partnerID=8YFLogxK
U2 - 10.1016/j.str.2022.12.006
DO - 10.1016/j.str.2022.12.006
M3 - Article
C2 - 36610391
AN - SCOPUS:85147029540
VL - 31
SP - 128-137.e5
JO - STRUCTURE
JF - STRUCTURE
SN - 0969-2126
IS - 2
ER -