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A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding

The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kina...

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Autores principales: Pflug, Alexander, Schimpl, Marianne, Nissink, J. Willem M., Overman, Ross C., Rawlins, Philip B., Truman, Caroline, Underwood, Elizabeth, Warwicker, Juli, Winter-Holt, Jon, McCoull, William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702301/
https://www.ncbi.nlm.nih.gov/pubmed/33119085
http://dx.doi.org/10.1042/BCJ20200735
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author Pflug, Alexander
Schimpl, Marianne
Nissink, J. Willem M.
Overman, Ross C.
Rawlins, Philip B.
Truman, Caroline
Underwood, Elizabeth
Warwicker, Juli
Winter-Holt, Jon
McCoull, William
author_facet Pflug, Alexander
Schimpl, Marianne
Nissink, J. Willem M.
Overman, Ross C.
Rawlins, Philip B.
Truman, Caroline
Underwood, Elizabeth
Warwicker, Juli
Winter-Holt, Jon
McCoull, William
author_sort Pflug, Alexander
collection PubMed
description The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here, we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor ‘example 172’ (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics, we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design.
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spelling pubmed-77023012020-12-08 A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding Pflug, Alexander Schimpl, Marianne Nissink, J. Willem M. Overman, Ross C. Rawlins, Philip B. Truman, Caroline Underwood, Elizabeth Warwicker, Juli Winter-Holt, Jon McCoull, William Biochem J Structural Biology The activation loop (A-loop) plays a key role in regulating the catalytic activity of protein kinases. Phosphorylation in this region enhances the phosphoryl transfer rate of the kinase domain and increases its affinity for ATP. Furthermore, the A-loop possesses autoinhibitory functions in some kinases, where it collapses onto the protein surface and blocks substrate binding when unphosphorylated. Due to its flexible nature, the A-loop is usually disordered and untraceable in kinase domain crystal structures. The resulting lack of structural information is regrettable as it impedes the design of drug A-loop contacts, which have proven favourable in multiple cases. Here, we characterize the binding with A-loop engagement between type 1.5 kinase inhibitor ‘example 172’ (EX172) and Mer tyrosine kinase (MerTK). With the help of crystal structures and binding kinetics, we portray how the recruitment of the A-loop elicits a two-step binding mechanism which results in a drug-target complex characterized by high affinity and long residence time. In addition, the type 1.5 compound possesses excellent kinome selectivity and a remarkable preference for the phosphorylated over the dephosphorylated form of MerTK. We discuss these unique characteristics in the context of known type 1 and type 2 inhibitors and highlight opportunities for future kinase inhibitor design. Portland Press Ltd. 2020-11-27 2020-11-27 /pmc/articles/PMC7702301/ /pubmed/33119085 http://dx.doi.org/10.1042/BCJ20200735 Text en © 2020 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Structural Biology
Pflug, Alexander
Schimpl, Marianne
Nissink, J. Willem M.
Overman, Ross C.
Rawlins, Philip B.
Truman, Caroline
Underwood, Elizabeth
Warwicker, Juli
Winter-Holt, Jon
McCoull, William
A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
title A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
title_full A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
title_fullStr A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
title_full_unstemmed A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
title_short A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
title_sort a-loop interactions in mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702301/
https://www.ncbi.nlm.nih.gov/pubmed/33119085
http://dx.doi.org/10.1042/BCJ20200735
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