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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University of Oxford
2018
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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. |
first_indexed | 2024-03-07T06:57:15Z |
format | Dataset |
id | oxford-uuid:fe8ae675-f572-4f76-a1e8-cf624838725a |
institution | University of Oxford |
last_indexed | 2024-03-07T06:57:15Z |
publishDate | 2018 |
publisher | University of Oxford |
record_format | dspace |
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 |