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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Conformational plasticity of the ULK3 kinase domain Sebastian Mathea , Eidarus Salah , Cynthia Tallant , Deep Chatterjee , Benedict-Tilman Berger , Rebecca Konietzny , Susanne Müller-Knapp , Benedikt M Kessler , Stefan Knapp Biochemical Journal DOI: 10.1042/BCJ20210257 Open Access Show Abstract ▼ Abstract: The human protein kinase ULK3 regulates the timing of membrane abscission, thus being involved in exosome budding and cytokinesis. Herein, we present the first high-resolution structures of the ULK3 kinase domain. Its unique features are explored against the background of other ULK kinases. An inhibitor fingerprint indicates that ULK3 is highly druggable and capable of adopting a wide range of conformations. In accordance with this, we describe a conformational switch between the active and an inactive ULK3 conformation, controlled by the properties of the attached small-molecule binder. Finally, we discuss a potential substrate-recognition mechanism of the full-length ULK3 protein.	Jun 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Lessons from LIMK1 enzymology and their impact on inhibitor design Eidarus Salah , Deep Chatterjee , Alessandra Beltrami , Anthony Tumber , Franziska Preuss , Peter Canning , Apirat Chaikuad , Petra Knaus , Stefan Knapp , Alex N. Bullock , Sebastian Mathea Biochemical Journal DOI: 10.1042/BCJ20190517 Diamond Proposal Number(s): [6391, 10619] Open Access Show Abstract ▼ 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.	Oct 2019

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