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Computational design of BclxL inhibitors that target transmembrane domain interactions
Several methods have been developed to explore interactions among water-soluble proteins or regions of proteins. However, techniques to target transmembrane domains (TMDs) have not been examined thoroughly despite their importance. Here, we developed a computational approach to design sequences that...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089226/ https://www.ncbi.nlm.nih.gov/pubmed/36881618 http://dx.doi.org/10.1073/pnas.2219648120 |
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author | Duart, Gerard Elazar, Assaf Weinstein, Jonathan Y. Gadea-Salom, Laura Ortiz-Mateu, Juan Fleishman, Sarel J. Mingarro, Ismael Martinez-Gil, Luis |
author_facet | Duart, Gerard Elazar, Assaf Weinstein, Jonathan Y. Gadea-Salom, Laura Ortiz-Mateu, Juan Fleishman, Sarel J. Mingarro, Ismael Martinez-Gil, Luis |
author_sort | Duart, Gerard |
collection | PubMed |
description | Several methods have been developed to explore interactions among water-soluble proteins or regions of proteins. However, techniques to target transmembrane domains (TMDs) have not been examined thoroughly despite their importance. Here, we developed a computational approach to design sequences that specifically modulate protein–protein interactions in the membrane. To illustrate this method, we demonstrated that BclxL can interact with other members of the B cell lymphoma 2 (Bcl2) family through the TMD and that these interactions are required for BclxL control of cell death. Next, we designed sequences that specifically recognize and sequester the TMD of BclxL. Hence, we were able to prevent BclxL intramembrane interactions and cancel its antiapoptotic effect. These results advance our understanding of protein–protein interactions in membranes and provide a means to modulate them. Moreover, the success of our approach may trigger the development of a generation of inhibitors targeting interactions between TMDs. |
format | Online Article Text |
id | pubmed-10089226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-100892262023-09-07 Computational design of BclxL inhibitors that target transmembrane domain interactions Duart, Gerard Elazar, Assaf Weinstein, Jonathan Y. Gadea-Salom, Laura Ortiz-Mateu, Juan Fleishman, Sarel J. Mingarro, Ismael Martinez-Gil, Luis Proc Natl Acad Sci U S A Biological Sciences Several methods have been developed to explore interactions among water-soluble proteins or regions of proteins. However, techniques to target transmembrane domains (TMDs) have not been examined thoroughly despite their importance. Here, we developed a computational approach to design sequences that specifically modulate protein–protein interactions in the membrane. To illustrate this method, we demonstrated that BclxL can interact with other members of the B cell lymphoma 2 (Bcl2) family through the TMD and that these interactions are required for BclxL control of cell death. Next, we designed sequences that specifically recognize and sequester the TMD of BclxL. Hence, we were able to prevent BclxL intramembrane interactions and cancel its antiapoptotic effect. These results advance our understanding of protein–protein interactions in membranes and provide a means to modulate them. Moreover, the success of our approach may trigger the development of a generation of inhibitors targeting interactions between TMDs. National Academy of Sciences 2023-03-07 2023-03-14 /pmc/articles/PMC10089226/ /pubmed/36881618 http://dx.doi.org/10.1073/pnas.2219648120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Duart, Gerard Elazar, Assaf Weinstein, Jonathan Y. Gadea-Salom, Laura Ortiz-Mateu, Juan Fleishman, Sarel J. Mingarro, Ismael Martinez-Gil, Luis Computational design of BclxL inhibitors that target transmembrane domain interactions |
title | Computational design of BclxL inhibitors that target transmembrane domain interactions |
title_full | Computational design of BclxL inhibitors that target transmembrane domain interactions |
title_fullStr | Computational design of BclxL inhibitors that target transmembrane domain interactions |
title_full_unstemmed | Computational design of BclxL inhibitors that target transmembrane domain interactions |
title_short | Computational design of BclxL inhibitors that target transmembrane domain interactions |
title_sort | computational design of bclxl inhibitors that target transmembrane domain interactions |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089226/ https://www.ncbi.nlm.nih.gov/pubmed/36881618 http://dx.doi.org/10.1073/pnas.2219648120 |
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