Dataset
LIM Domain Kinase 1 (LIMK1), Human Kinase Domain; A Target Enabling Package
- Documentation:
- 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.
- Version:
- 3
Actions
Authors/Creators
Contributors
+ Mathea, S
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Role:
- Researcher
+ Salah, E
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Organic Chemistry
- Role:
- Researcher
- ORCID:
- 0000-0001-7552-4966
+ Knapp, S
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Structural Genomics Consortium
- Role:
- Researcher
+ Beltrami, A
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Structural Genomics Consortium
- Role:
- Researcher
+ Chaikuad, A
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- Structural Genomics Consortium
- Role:
- Researcher
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 106169/ZZ14/Z
- Publisher:
- University of Oxford
- Publication date:
- 2018
- Version number:
- 3
- Language:
-
English
- Keywords:
- Subjects:
- Pubs id:
-
1480281
- UUID:
-
uuid:6fc2d646-a99d-477a-bdc0-187c6047ebb0
- Local pid:
-
pubs:1480281
- Deposit date:
-
2018-05-08
Terms of use
- Copyright date:
- 2018
- Notes:
- This document represents version 3 of the TEP datasheet and includes all updates on the project as of April 2018. For more information about TEPs and the TEP Programme, please visit https://thesgc.org/tep.
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