LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package

A description of the materials and methods is included within the TEP datasheet. Loss of the translational repressor FMRP in fragile X syndrome causes upregulation of the type II BMP receptor BMPR2 and its non-canonical signalling via the kinase LIMK1. LIMK1 performs inhibitory phosphorylation on co...

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Main Author: Mathea, S
Format: Dataset
Published: University of Oxford 2018
Subjects:
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author Mathea, S
author2 Mathea, S
author_facet Mathea, S
Mathea, S
author_sort Mathea, S
collection OXFORD
description A description of the materials and methods is included within the TEP datasheet. Loss of the translational repressor FMRP in fragile X syndrome causes upregulation of the type II BMP receptor BMPR2 and its non-canonical signalling via the kinase LIMK1. LIMK1 performs inhibitory phosphorylation on cofilin proteins blocking their actin-severing activity. Excessive BMPR2-LIMK1 activation was associated with dendritic spine and behavioural defects in animal models that could be rescued by BMPR2 knockdown or LIMK1 inhibition. Here we present a target enabling package for the therapeutic target LIMK1. We include crystal structures of BMPR2, LIMK1, LIMK2 and the LIMK1-cofilin complex, as well as multiple assays for small molecule inhibitor screening. Finally, we identify a series of allosteric LIMK1 inhibitors with promising potency and selectivity that may potentially allow the development of a safe drug for this chronic indication.
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spelling oxford-uuid:fe8ae675-f572-4f76-a1e8-cf624838725a2022-03-27T13:37:32ZLIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling PackageDatasethttp://purl.org/coar/resource_type/c_ddb1uuid:fe8ae675-f572-4f76-a1e8-cf624838725aStructural GenomicsDrug DiscoveryChemical BiologyORA DepositUniversity of Oxford2018Mathea, SMathea, SBullock, ASalah, EKnapp, SBeltrami, AChaikuad, AHanke, TKashima, RCanning, PMuller-Knapp, SKnaus, PHata, AA description of the materials and methods is included within the TEP datasheet. Loss of the translational repressor FMRP in fragile X syndrome causes upregulation of the type II BMP receptor BMPR2 and its non-canonical signalling via the kinase LIMK1. LIMK1 performs inhibitory phosphorylation on cofilin proteins blocking their actin-severing activity. Excessive BMPR2-LIMK1 activation was associated with dendritic spine and behavioural defects in animal models that could be rescued by BMPR2 knockdown or LIMK1 inhibition. Here we present a target enabling package for the therapeutic target LIMK1. We include crystal structures of BMPR2, LIMK1, LIMK2 and the LIMK1-cofilin complex, as well as multiple assays for small molecule inhibitor screening. Finally, we identify a series of allosteric LIMK1 inhibitors with promising potency and selectivity that may potentially allow the development of a safe drug for this chronic indication.
spellingShingle Structural Genomics
Drug Discovery
Chemical Biology
Mathea, S
LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package
title LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package
title_full LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package
title_fullStr LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package
title_full_unstemmed LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package
title_short LIM Domain Kinase 1 (LIMK1), human kinase domain; A Target Enabling Package
title_sort lim domain kinase 1 limk1 human kinase domain a target enabling package
topic Structural Genomics
Drug Discovery
Chemical Biology
work_keys_str_mv AT matheas limdomainkinase1limk1humankinasedomainatargetenablingpackage