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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...

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Autores principales: Duart, Gerard, Elazar, Assaf, Weinstein, Jonathan Y., Gadea-Salom, Laura, Ortiz-Mateu, Juan, Fleishman, Sarel J., Mingarro, Ismael, Martinez-Gil, Luis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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