Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases

Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations...

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Autores principales: Zelnik, Iris D., Mestre, Beatriz, Weinstein, Jonathan J., Dingjan, Tamir, Izrailov, Stav, Ben-Dor, Shifra, Fleishman, Sarel J., Futerman, Anthony H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122649/
https://www.ncbi.nlm.nih.gov/pubmed/37087500
http://dx.doi.org/10.1038/s41467-023-38047-x
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author Zelnik, Iris D.
Mestre, Beatriz
Weinstein, Jonathan J.
Dingjan, Tamir
Izrailov, Stav
Ben-Dor, Shifra
Fleishman, Sarel J.
Futerman, Anthony H.
author_facet Zelnik, Iris D.
Mestre, Beatriz
Weinstein, Jonathan J.
Dingjan, Tamir
Izrailov, Stav
Ben-Dor, Shifra
Fleishman, Sarel J.
Futerman, Anthony H.
author_sort Zelnik, Iris D.
collection PubMed
description Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.
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spelling pubmed-101226492023-04-24 Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases Zelnik, Iris D. Mestre, Beatriz Weinstein, Jonathan J. Dingjan, Tamir Izrailov, Stav Ben-Dor, Shifra Fleishman, Sarel J. Futerman, Anthony H. Nat Commun Article Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases. Nature Publishing Group UK 2023-04-22 /pmc/articles/PMC10122649/ /pubmed/37087500 http://dx.doi.org/10.1038/s41467-023-38047-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zelnik, Iris D.
Mestre, Beatriz
Weinstein, Jonathan J.
Dingjan, Tamir
Izrailov, Stav
Ben-Dor, Shifra
Fleishman, Sarel J.
Futerman, Anthony H.
Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
title Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
title_full Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
title_fullStr Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
title_full_unstemmed Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
title_short Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
title_sort computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122649/
https://www.ncbi.nlm.nih.gov/pubmed/37087500
http://dx.doi.org/10.1038/s41467-023-38047-x
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