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Nucleotide-binding mechanisms in pseudokinases

Pseudokinases are classified by the lack of one or several of the highly conserved motifs involved in nucleotide (nt) binding or catalytic activity of protein kinases (PKs). Pseudokinases represent ∼10% of the human kinome and they are found in all evolutionary classes of kinases. It has become evid...

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Autores principales: Hammarén, Henrik M., Virtanen, Anniina T., Silvennoinen, Olli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718504/
https://www.ncbi.nlm.nih.gov/pubmed/26589967
http://dx.doi.org/10.1042/BSR20150226
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author Hammarén, Henrik M.
Virtanen, Anniina T.
Silvennoinen, Olli
author_facet Hammarén, Henrik M.
Virtanen, Anniina T.
Silvennoinen, Olli
author_sort Hammarén, Henrik M.
collection PubMed
description Pseudokinases are classified by the lack of one or several of the highly conserved motifs involved in nucleotide (nt) binding or catalytic activity of protein kinases (PKs). Pseudokinases represent ∼10% of the human kinome and they are found in all evolutionary classes of kinases. It has become evident that pseudokinases, which were initially considered somewhat peculiar dead kinases, are important components in several signalling cascades. Furthermore, several pseudokinases have been linked to human diseases, particularly cancer, which is raising interest for therapeutic approaches towards these proteins. The ATP-binding pocket is a well-established drug target and elucidation of the mechanism and properties of nt binding in pseudokinases is of significant interest and importance. Recent studies have demonstrated that members of the pseudokinase family are very diverse in structure as well as in their ability and mechanism to bind nts or perform phosphoryl transfer reactions. This diversity also precludes prediction of pseudokinase function, or the importance of nt binding for said function, based on primary sequence alone. Currently available data indicate that ∼40% of pseudokinases are able to bind nts, whereas only few are able to catalyse occasional phosphoryl transfer. Pseudokinases employ diverse mechanisms to bind nts, which usually occurs at low, but physiological, affinity. ATP binding serves often a structural role but in most cases the functional roles are not precisely known. In the present review, we discuss the various mechanisms that pseudokinases employ for nt binding and how this often low-affinity binding can be accurately analysed.
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spelling pubmed-47185042016-02-02 Nucleotide-binding mechanisms in pseudokinases Hammarén, Henrik M. Virtanen, Anniina T. Silvennoinen, Olli Biosci Rep Review Articles Pseudokinases are classified by the lack of one or several of the highly conserved motifs involved in nucleotide (nt) binding or catalytic activity of protein kinases (PKs). Pseudokinases represent ∼10% of the human kinome and they are found in all evolutionary classes of kinases. It has become evident that pseudokinases, which were initially considered somewhat peculiar dead kinases, are important components in several signalling cascades. Furthermore, several pseudokinases have been linked to human diseases, particularly cancer, which is raising interest for therapeutic approaches towards these proteins. The ATP-binding pocket is a well-established drug target and elucidation of the mechanism and properties of nt binding in pseudokinases is of significant interest and importance. Recent studies have demonstrated that members of the pseudokinase family are very diverse in structure as well as in their ability and mechanism to bind nts or perform phosphoryl transfer reactions. This diversity also precludes prediction of pseudokinase function, or the importance of nt binding for said function, based on primary sequence alone. Currently available data indicate that ∼40% of pseudokinases are able to bind nts, whereas only few are able to catalyse occasional phosphoryl transfer. Pseudokinases employ diverse mechanisms to bind nts, which usually occurs at low, but physiological, affinity. ATP binding serves often a structural role but in most cases the functional roles are not precisely known. In the present review, we discuss the various mechanisms that pseudokinases employ for nt binding and how this often low-affinity binding can be accurately analysed. Portland Press Ltd. 2016-01-15 /pmc/articles/PMC4718504/ /pubmed/26589967 http://dx.doi.org/10.1042/BSR20150226 Text en © 2016 Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0 (http://creativecommons.org/licenses/by/3.0/) .
spellingShingle Review Articles
Hammarén, Henrik M.
Virtanen, Anniina T.
Silvennoinen, Olli
Nucleotide-binding mechanisms in pseudokinases
title Nucleotide-binding mechanisms in pseudokinases
title_full Nucleotide-binding mechanisms in pseudokinases
title_fullStr Nucleotide-binding mechanisms in pseudokinases
title_full_unstemmed Nucleotide-binding mechanisms in pseudokinases
title_short Nucleotide-binding mechanisms in pseudokinases
title_sort nucleotide-binding mechanisms in pseudokinases
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718504/
https://www.ncbi.nlm.nih.gov/pubmed/26589967
http://dx.doi.org/10.1042/BSR20150226
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