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Towards Unraveling the Histone Code by Fragment Blind Docking

Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation wi...

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Autores principales: Bálint, Mónika, Horváth, István, Mészáros, Nikolett, Hetényi, Csaba
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358888/
https://www.ncbi.nlm.nih.gov/pubmed/30669446
http://dx.doi.org/10.3390/ijms20020422
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author Bálint, Mónika
Horváth, István
Mészáros, Nikolett
Hetényi, Csaba
author_facet Bálint, Mónika
Horváth, István
Mészáros, Nikolett
Hetényi, Csaba
author_sort Bálint, Mónika
collection PubMed
description Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques. Calculation of such complexes is difficult due to considerable size and flexibility of peptides and the shallow binding surfaces of the readers. Moreover, location of the binding sites is often unknown, which requires a blind docking search over the entire surface of the target protein. To accelerate the work in this field, a new approach is presented for prediction of the structure of histone H3 peptide tails docked to their targets. Using a fragmenting protocol and a systematic blind docking method, a collection of well-positioned fragments of the H3 peptide is produced. After linking the fragments, reconstitution of anchoring regions of the target-bound H3 peptide conformations was possible. As a first attempt of combination of blind and fragment docking approaches, our new method is named fragment blind docking (FBD).
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spelling pubmed-63588882019-02-06 Towards Unraveling the Histone Code by Fragment Blind Docking Bálint, Mónika Horváth, István Mészáros, Nikolett Hetényi, Csaba Int J Mol Sci Article Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques. Calculation of such complexes is difficult due to considerable size and flexibility of peptides and the shallow binding surfaces of the readers. Moreover, location of the binding sites is often unknown, which requires a blind docking search over the entire surface of the target protein. To accelerate the work in this field, a new approach is presented for prediction of the structure of histone H3 peptide tails docked to their targets. Using a fragmenting protocol and a systematic blind docking method, a collection of well-positioned fragments of the H3 peptide is produced. After linking the fragments, reconstitution of anchoring regions of the target-bound H3 peptide conformations was possible. As a first attempt of combination of blind and fragment docking approaches, our new method is named fragment blind docking (FBD). MDPI 2019-01-19 /pmc/articles/PMC6358888/ /pubmed/30669446 http://dx.doi.org/10.3390/ijms20020422 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bálint, Mónika
Horváth, István
Mészáros, Nikolett
Hetényi, Csaba
Towards Unraveling the Histone Code by Fragment Blind Docking
title Towards Unraveling the Histone Code by Fragment Blind Docking
title_full Towards Unraveling the Histone Code by Fragment Blind Docking
title_fullStr Towards Unraveling the Histone Code by Fragment Blind Docking
title_full_unstemmed Towards Unraveling the Histone Code by Fragment Blind Docking
title_short Towards Unraveling the Histone Code by Fragment Blind Docking
title_sort towards unraveling the histone code by fragment blind docking
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358888/
https://www.ncbi.nlm.nih.gov/pubmed/30669446
http://dx.doi.org/10.3390/ijms20020422
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