Human LIM Domain Kinase 1 (LIMK1), Kinase DomainThe content of this page was edited by SGC and matteoferla on the 2019-10-07 15:59:06.794382.
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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.
Structures available in TEP:
- BMPR2 + ADP/Mg2+ (PDB:3G2F ): ,
- LIMK1 + staurosporine (PDB:3S95 ): ,
- LIMK1 + PF-477736 (PDB:5NXC ): ,
- LIMK1 + ATPγS + Cofilin (PDB:5L6W ): ,
- LIMK2 + TH300 (PDB:5NXD ): ,