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Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins
Three protein targets from SARS-CoV-2, the viral pathogen that causes COVID-19, are studied: the main protease, the 2′-O-RNA methyltransferase, and the nucleocapsid (N) protein. For the main protease, the nucleophilicity of the catalytic cysteine C145 is enabled by coupling to three histidine residu...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9659918/ https://www.ncbi.nlm.nih.gov/pubmed/36385993 http://dx.doi.org/10.3389/fchem.2022.1017394 |
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author | Iyengar, Suhasini M. Barnsley, Kelly K. Vu, Hoang Yen Bongalonta, Ian Jef A. Herrod, Alyssa S. Scott, Jasmine A. Ondrechen, Mary Jo |
author_facet | Iyengar, Suhasini M. Barnsley, Kelly K. Vu, Hoang Yen Bongalonta, Ian Jef A. Herrod, Alyssa S. Scott, Jasmine A. Ondrechen, Mary Jo |
author_sort | Iyengar, Suhasini M. |
collection | PubMed |
description | Three protein targets from SARS-CoV-2, the viral pathogen that causes COVID-19, are studied: the main protease, the 2′-O-RNA methyltransferase, and the nucleocapsid (N) protein. For the main protease, the nucleophilicity of the catalytic cysteine C145 is enabled by coupling to three histidine residues, H163 and H164 and catalytic dyad partner H41. These electrostatic couplings enable significant population of the deprotonated state of C145. For the RNA methyltransferase, the catalytic lysine K6968 that serves as a Brønsted base has significant population of its deprotonated state via strong coupling with K6844 and Y6845. For the main protease, Partial Order Optimum Likelihood (POOL) predicts two clusters of biochemically active residues; one includes the catalytic H41 and C145 and neighboring residues. The other surrounds a second pocket adjacent to the catalytic site and includes S1 residues F140, L141, H163, E166, and H172 and also S2 residue D187. This secondary recognition site could serve as an alternative target for the design of molecular probes. From in silico screening of library compounds, ligands with predicted affinity for the secondary site are reported. For the NSP16-NSP10 complex that comprises the RNA methyltransferase, three different sites are predicted. One is the catalytic core at the conserved K-D-K-E motif that includes catalytic residues D6928, K6968, and E7001 plus K6844. The second site surrounds the catalytic core and consists of Y6845, C6849, I6866, H6867, F6868, V6894, D6895, D6897, I6926, S6927, Y6930, and K6935. The third is located at the heterodimer interface. Ligands predicted to have high affinity for the first or second sites are reported. Three sites are also predicted for the nucleocapsid protein. This work uncovers key interactions that contribute to the function of the three viral proteins and also suggests alternative sites for ligand design. |
format | Online Article Text |
id | pubmed-9659918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96599182022-11-15 Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins Iyengar, Suhasini M. Barnsley, Kelly K. Vu, Hoang Yen Bongalonta, Ian Jef A. Herrod, Alyssa S. Scott, Jasmine A. Ondrechen, Mary Jo Front Chem Chemistry Three protein targets from SARS-CoV-2, the viral pathogen that causes COVID-19, are studied: the main protease, the 2′-O-RNA methyltransferase, and the nucleocapsid (N) protein. For the main protease, the nucleophilicity of the catalytic cysteine C145 is enabled by coupling to three histidine residues, H163 and H164 and catalytic dyad partner H41. These electrostatic couplings enable significant population of the deprotonated state of C145. For the RNA methyltransferase, the catalytic lysine K6968 that serves as a Brønsted base has significant population of its deprotonated state via strong coupling with K6844 and Y6845. For the main protease, Partial Order Optimum Likelihood (POOL) predicts two clusters of biochemically active residues; one includes the catalytic H41 and C145 and neighboring residues. The other surrounds a second pocket adjacent to the catalytic site and includes S1 residues F140, L141, H163, E166, and H172 and also S2 residue D187. This secondary recognition site could serve as an alternative target for the design of molecular probes. From in silico screening of library compounds, ligands with predicted affinity for the secondary site are reported. For the NSP16-NSP10 complex that comprises the RNA methyltransferase, three different sites are predicted. One is the catalytic core at the conserved K-D-K-E motif that includes catalytic residues D6928, K6968, and E7001 plus K6844. The second site surrounds the catalytic core and consists of Y6845, C6849, I6866, H6867, F6868, V6894, D6895, D6897, I6926, S6927, Y6930, and K6935. The third is located at the heterodimer interface. Ligands predicted to have high affinity for the first or second sites are reported. Three sites are also predicted for the nucleocapsid protein. This work uncovers key interactions that contribute to the function of the three viral proteins and also suggests alternative sites for ligand design. Frontiers Media S.A. 2022-10-31 /pmc/articles/PMC9659918/ /pubmed/36385993 http://dx.doi.org/10.3389/fchem.2022.1017394 Text en Copyright © 2022 Iyengar, Barnsley, Vu, Bongalonta, Herrod, Scott and Ondrechen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Iyengar, Suhasini M. Barnsley, Kelly K. Vu, Hoang Yen Bongalonta, Ian Jef A. Herrod, Alyssa S. Scott, Jasmine A. Ondrechen, Mary Jo Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins |
title | Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins |
title_full | Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins |
title_fullStr | Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins |
title_full_unstemmed | Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins |
title_short | Identification and characterization of alternative sites and molecular probes for SARS-CoV-2 target proteins |
title_sort | identification and characterization of alternative sites and molecular probes for sars-cov-2 target proteins |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9659918/ https://www.ncbi.nlm.nih.gov/pubmed/36385993 http://dx.doi.org/10.3389/fchem.2022.1017394 |
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