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Lessons from LIMK1 enzymology and their impact on inhibitor design
Authors:
Eidarus
Salah
(Target Discovery Institute; Structural Genomics Consortium, University of Oxford)
,
Deep
Chatterjee
(Structural Genomics Consortium, Goethe-University Frankfurt)
,
Alessandra
Beltrami
(Structural Genomics Consortium, University of Oxford)
,
Anthony
Tumber
(Target Discovery Institute; Structural Genomics Consortium, University of Oxford)
,
Franziska
Preuss
(Structural Genomics Consortium, Goethe-University Frankfurt)
,
Peter
Canning
(Structural Genomics Consortium, University of Oxford)
,
Apirat
Chaikuad
(Structural Genomics Consortium, Goethe-University Frankfurt)
,
Petra
Knaus
(Freie Universität Berlin)
,
Stefan
Knapp
(Structural Genomics Consortium, Goethe-University Frankfurt)
,
Alex N.
Bullock
(Structural Genomics Consortium, University of Oxford)
,
Sebastian
Mathea
(Structural Genomics Consortium, University of Oxford; Goethe-University Frankfurt)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Biochemical Journal
State:
Published (Approved)
Published:
October 2019
Diamond Proposal Number(s):
6391
,
10619

Abstract: 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.
Journal Keywords: Kinase; Small-molecule inhibitors; Reaction mechanism; Substrate recognition; LIMK1
Diamond Keywords: Enzymes
Subject Areas:
Biology and Bio-materials,
Chemistry
Instruments:
I02-Macromolecular Crystallography
,
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Added On:
22/10/2019 09:09
Documents:
fhh444bbfff.pdf
Discipline Tags:
Biochemistry
Chemistry
Structural biology
Biophysics
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)