Lessons from LIMK1 enzymology and their impact on inhibitor design.
LIMK1
kinase
reaction mechanism
small-molecule inhibitors
substrate recognition
Journal
The Biochemical journal
ISSN: 1470-8728
Titre abrégé: Biochem J
Pays: England
ID NLM: 2984726R
Informations de publication
Date de publication:
15 11 2019
15 11 2019
Historique:
received:
15
07
2019
revised:
07
10
2019
accepted:
11
10
2019
pubmed:
28
10
2019
medline:
9
7
2020
entrez:
26
10
2019
Statut:
ppublish
Résumé
LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique 'rock-and-poke' mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding.
Identifiants
pubmed: 31652302
pii: 220756
doi: 10.1042/BCJ20190517
pmc: PMC6835155
doi:
Substances chimiques
Protein Kinase Inhibitors
0
LIMK1 protein, human
EC 2.7.11.1
LIMK2 protein, human
EC 2.7.11.1
Lim Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3197-3209Informations de copyright
© 2019 The Author(s).
Références
Acta Crystallogr D Biol Crystallogr. 2005 Apr;61(Pt 4):458-64
pubmed: 15805601
ACS Med Chem Lett. 2014 Nov 24;6(1):84-8
pubmed: 25589936
Oncotarget. 2017 Jun 20;8(25):41749-41763
pubmed: 28445157
J Neurol Neurosurg Psychiatry. 2017 Jul;88(7):557-563
pubmed: 28285264
Curr Genomics. 2011 May;12(3):216-24
pubmed: 22043169
Sci Signal. 2016 Jun 07;9(431):ra58
pubmed: 27273096
Dev Biol. 2002 Jan 15;241(2):259-72
pubmed: 11784110
Mol Biol Cell. 2001 Apr;12(4):1131-45
pubmed: 11294912
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Mol Cancer Ther. 2008 Nov;7(11):3490-8
pubmed: 19001433
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
pubmed: 15299926
Mol Cell. 2014 Jan 9;53(1):140-7
pubmed: 24374310
Cell. 2015 Jul 2;162(1):146-59
pubmed: 26140595
Oncogene. 1995 Oct 5;11(7):1271-81
pubmed: 7478547
J Cell Biol. 2010 Oct 4;191(1):169-85
pubmed: 20876278
Nature. 1998 Jun 25;393(6687):805-9
pubmed: 9655397
Nat Neurosci. 2016 Dec;19(12):1610-1618
pubmed: 27723745
Neuron. 2011 Oct 20;72(2):245-56
pubmed: 21944778
Cell. 2002 Jan 25;108(2):233-46
pubmed: 11832213
Dev Growth Differ. 2015 May;57(4):275-90
pubmed: 25864508
Mol Cancer Ther. 2008 Aug;7(8):2394-404
pubmed: 18723486
Biochem Biophys Res Commun. 1986 Mar 13;135(2):397-402
pubmed: 3457562
Nat Protoc. 2007;2(9):2212-21
pubmed: 17853878
Surg Neurol Int. 2015 Nov 16;6:171
pubmed: 26629397
J Physiol. 2018 Jul;596(14):2773-2782
pubmed: 29380377
Methods Mol Biol. 2014;1091:95-121
pubmed: 24203326
J Cell Sci. 2016 Sep 1;129(17):3211-8
pubmed: 27505888
Cancer Res. 2012 Sep 1;72(17):4429-39
pubmed: 22761334
Neuroscientist. 2018 Feb;24(1):54-72
pubmed: 28459188
Mol Cell. 2016 May 5;62(3):397-408
pubmed: 27153537
Br J Pharmacol. 2018 Jun;175(11):2077-2096
pubmed: 29574791
Nat Rev Mol Cell Biol. 2007 Jul;8(7):530-41
pubmed: 17585314
Nat Cell Biol. 1999 Sep;1(5):253-9
pubmed: 10559936
Methods Mol Biol. 2014;1091:73-94
pubmed: 24203325
Sci Signal. 2017 May 02;10(477):null
pubmed: 28465421
Methods Mol Biol. 2014;1091:55-72
pubmed: 24203324
PLoS One. 2012;7(10):e47168
pubmed: 23071748
Neuropharmacology. 2004 Oct;47(5):746-54
pubmed: 15458846