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Crystal structure of the human PRPK–TPRKB complex

Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers. We have previously shown that small compounds targeting PRPK showed anti-cancer activity against colon and skin cancer. Here we present...

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Autores principales: Li, Jian, Ma, Xinli, Banerjee, Surajit, Chen, Hanyong, Ma, Weiya, Bode, Ann M., Dong, Zigang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864929/
https://www.ncbi.nlm.nih.gov/pubmed/33547416
http://dx.doi.org/10.1038/s42003-021-01683-4
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author Li, Jian
Ma, Xinli
Banerjee, Surajit
Chen, Hanyong
Ma, Weiya
Bode, Ann M.
Dong, Zigang
author_facet Li, Jian
Ma, Xinli
Banerjee, Surajit
Chen, Hanyong
Ma, Weiya
Bode, Ann M.
Dong, Zigang
author_sort Li, Jian
collection PubMed
description Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers. We have previously shown that small compounds targeting PRPK showed anti-cancer activity against colon and skin cancer. Here we present the 2.53 Å crystal structure of the human PRPK-TPRKB-AMPPNP (adenylyl-imidodiphosphate) complex. The structure reveals details in PRPK-AMPPNP coordination and PRPK-TPRKB interaction. PRPK appears in an active conformation, albeit lacking the conventional kinase activation loop. We constructed a structural model of the human EKC/KEOPS complex, composed of PRPK, TPRKB, OSGEP, LAGE3, and GON7. Disease mutations in PRPK and TPRKB are mapped into the structure, and we show that one mutation, PRPK K238Nfs*2, lost the binding to OSGEP. Our structure also makes the virtual screening possible and paves the way for more rational drug design.
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spelling pubmed-78649292021-02-16 Crystal structure of the human PRPK–TPRKB complex Li, Jian Ma, Xinli Banerjee, Surajit Chen, Hanyong Ma, Weiya Bode, Ann M. Dong, Zigang Commun Biol Article Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers. We have previously shown that small compounds targeting PRPK showed anti-cancer activity against colon and skin cancer. Here we present the 2.53 Å crystal structure of the human PRPK-TPRKB-AMPPNP (adenylyl-imidodiphosphate) complex. The structure reveals details in PRPK-AMPPNP coordination and PRPK-TPRKB interaction. PRPK appears in an active conformation, albeit lacking the conventional kinase activation loop. We constructed a structural model of the human EKC/KEOPS complex, composed of PRPK, TPRKB, OSGEP, LAGE3, and GON7. Disease mutations in PRPK and TPRKB are mapped into the structure, and we show that one mutation, PRPK K238Nfs*2, lost the binding to OSGEP. Our structure also makes the virtual screening possible and paves the way for more rational drug design. Nature Publishing Group UK 2021-02-05 /pmc/articles/PMC7864929/ /pubmed/33547416 http://dx.doi.org/10.1038/s42003-021-01683-4 Text en © The Author(s) 2021 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/.
spellingShingle Article
Li, Jian
Ma, Xinli
Banerjee, Surajit
Chen, Hanyong
Ma, Weiya
Bode, Ann M.
Dong, Zigang
Crystal structure of the human PRPK–TPRKB complex
title Crystal structure of the human PRPK–TPRKB complex
title_full Crystal structure of the human PRPK–TPRKB complex
title_fullStr Crystal structure of the human PRPK–TPRKB complex
title_full_unstemmed Crystal structure of the human PRPK–TPRKB complex
title_short Crystal structure of the human PRPK–TPRKB complex
title_sort crystal structure of the human prpk–tprkb complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864929/
https://www.ncbi.nlm.nih.gov/pubmed/33547416
http://dx.doi.org/10.1038/s42003-021-01683-4
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