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Title: Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10.

Abstract

No abstract prepared.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Ministry of Science and Technology of China; NSFC; Sino-German Center; Sino-European Project; European Commission (EC)
OSTI Identifier:
928667
Report Number(s):
ANL/BIO/JA-61349
Journal ID: ISSN 0022-538X; JOVIAM; TRN: US200812%%329
DOE Contract Number:
DE-AC02-06CH11357
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. of Virol.; Journal Volume: 80; Journal Issue: 16 ; 2006
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; PROTEIN STRUCTURE; VIRUSES; RESPIRATORY SYSTEM; MOLECULAR STRUCTURE

Citation Formats

Su, D., Lou, Z., Sun, F., Zhai, Y., Yang, H., Zhang, R., Joachimiak, A., Zhang, X., Bartlam, M., Rao, Z., Biosciences Division, Tsinghua Univ., Chinese Academy of Sciences, and Oklahoma Medical Research Foundation. Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10.. United States: N. p., 2006. Web. doi:10.1128/JVI.00483-06.
Su, D., Lou, Z., Sun, F., Zhai, Y., Yang, H., Zhang, R., Joachimiak, A., Zhang, X., Bartlam, M., Rao, Z., Biosciences Division, Tsinghua Univ., Chinese Academy of Sciences, & Oklahoma Medical Research Foundation. Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10.. United States. doi:10.1128/JVI.00483-06.
Su, D., Lou, Z., Sun, F., Zhai, Y., Yang, H., Zhang, R., Joachimiak, A., Zhang, X., Bartlam, M., Rao, Z., Biosciences Division, Tsinghua Univ., Chinese Academy of Sciences, and Oklahoma Medical Research Foundation. Sun . "Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10.". United States. doi:10.1128/JVI.00483-06.
@article{osti_928667,
title = {Dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp10.},
author = {Su, D. and Lou, Z. and Sun, F. and Zhai, Y. and Yang, H. and Zhang, R. and Joachimiak, A. and Zhang, X. and Bartlam, M. and Rao, Z. and Biosciences Division and Tsinghua Univ. and Chinese Academy of Sciences and Oklahoma Medical Research Foundation},
abstractNote = {No abstract prepared.},
doi = {10.1128/JVI.00483-06},
journal = {J. of Virol.},
number = 16 ; 2006,
volume = 80,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}
  • No abstract prepared.
  • The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC{sub 50} = 0.56 {mu}M; antiviral EC{sub 50} = 9.1 {mu}M) and the corresponding (R)-Me 15g (IC{sub 50} = 0.32 {mu}M; antiviral EC{sub 50} = 9.1more » {mu}M) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.« less
  • The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) is responsible for host cell attachment and fusion of the viral and host cell membranes. Within S the receptor binding domain (RBD) mediates the interaction with angiotensin-converting enzyme 2 (ACE2), the SARS-CoV host cell receptor. Both S and the RBD are highly immunogenic and both have been found to elicit neutralizing antibodies. Reported here is the X-ray crystal structure of the RBD in complex with the Fab of a neutralizing mouse monoclonal antibody, F26G19, elicited by immunization with chemically inactivated SARS-CoV. The RBD-F26G19 Fab complex represents the firstmore » example of the structural characterization of an antibody elicited by an immune response to SARS-CoV or any fragment of it. The structure reveals that the RBD surface recognized by F26G19 overlaps significantly with the surface recognized by ACE2 and, as such, suggests that F26G19 likely neutralizes SARS-CoV by blocking the virus-host cell interaction.« less
  • Mature nonstructural protein-15 (nsp15) from the severe acute respiratory syndrome coronavirus (SARS-CoV) contains a novel uridylate-specific Mn{sup 2+}-dependent endoribonuclease (NendoU). Structure studies of the full-length form of the obligate hexameric enzyme from two CoVs, SARS-CoV and murine hepatitis virus, and its monomeric homologue, XendoU from Xenopus laevis, combined with mutagenesis studies have implicated several residues in enzymatic activity and the N-terminal domain as the major determinant of hexamerization. However, the tight link between hexamerization and enzyme activity in NendoUs has remained an enigma. Here, we report the structure of a trimmed, monomeric form of SARS-CoV nsp15 (residues 28 to 335)more » determined to a resolution of 2.9 Angstroms. The catalytic loop (residues 234 to 249) with its two reactive histidines (His 234 and His 249) is dramatically flipped by {approx}120 degrees into the active site cleft. Furthermore, the catalytic nucleophile Lys 289 points in a diametrically opposite direction, a consequence of an outward displacement of the supporting loop (residues 276 to 295). In the full-length hexameric forms, these two loops are packed against each other and are stabilized by intimate intersubunit interactions. Our results support the hypothesis that absence of an adjacent monomer due to deletion of the hexamerization domain is the most likely cause for disruption of the active site, offering a structural basis for why only the hexameric form of this enzyme is active.« less
  • A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). But, unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure–activity relationships within S1', S1, and S2enzyme binding pockets. Moreover, the X-ray structure of SARS-CoV 3CLpromore » bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.« less