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Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography	Synthesis and structure–activity relationships of 3,5-disubstituted-pyrrolo[2,3- b ]pyridines as inhibitors of adaptor-associated kinase 1 with antiviral activity Sven Verdonck , Szu-yuan Pu , Fiona J. Sorrell , Jon M. Elkins , Mathy Froeyen , Ling-jie Gao , Laura I. Prugar , Danielle E. Dorosky , Jennifer M. Brannan , Rina Barouch-bentov , Stefan Knapp , John M. Dye , Piet Herdewijn , Shirit Einav , Steven De Jonghe Journal Of Medicinal Chemistry 62, 5810 - 5831 DOI: 10.1021/acs.jmedchem.9b00136 Diamond Proposal Number(s): [10619] Show Abstract ▼ Abstract: There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine–threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3-b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.	May 2019
B21-High Throughput SAXS I03-Macromolecular Crystallography	Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis Fiona J. Sorrell , Lena M. Kilian , Jonathan M. Elkins Biochemical Journal 476, 1037 - 1051 DOI: 10.1042/BCJ20180867 Open Access Show Abstract ▼ Abstract: The group A p21-activated kinases (PAKs) exist in an auto-inhibited form until activated by GTPase binding and auto-phosphorylation. In the auto-inhibited form a regulatory domain binds to the kinase domain blocking the binding of substrates, and CDC42 or Rac binding to the regulatory domain relieves this auto-inhibition allowing auto-phosphorylation on the kinase domain activation loop. We have determined the crystal structure of the PAK3 catalytic domain and by small angle X-ray scattering the solution-phase structures of full-length inactive PAK1 and PAK3. The structures reveal a compact but elongated molecular shape that demonstrates that, together with multiple independent biophysical measurements and in contrast to previous assumptions, group A PAKs are monomeric both before and after activation, consistent with an activation mechanism of cis -autoinhibition and initial cis -autophosphorylation, followed by transient dimerization to allow trans- autophosphorylation for full activation, yielding a monomeric active PAK protein.	Apr 2019
I02-Macromolecular Crystallography	WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop Megan J. Agajanian , Matthew P. Walker , Alison D. Axtman , Roberta R. Ruela-de-sousa , D. Stephen Serafin , Alex D. Rabinowitz , David M. Graham , Meagan B. Ryan , Tigist Tamir , Yuko Nakamichi , Melissa V. Gammons , James M. Bennett , Rafael M. Counago , David H. Drewry , Jonathan M. Elkins , Carina Gileadi , Opher Gileadi , Paulo H. Godoi , Nirav Kapadia , Susanne Müller , André S. Santiago , Fiona J. Sorrell , Carrow I. Wells , Oleg Fedorov , Timothy M. Willson , William J. Zuercher , Michael B. Major Cell Reports 26, 79 - 93.e8 DOI: 10.1016/j.celrep.2018.12.023 Open Access Show Abstract ▼ Abstract: β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity.	Jan 2019
B21-High Throughput SAXS I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structural Complexity in the KCTD Family of Cullin3-Dependent E3 Ubiquitin Ligases Daniel M. Pinkas , Caroline E. Sanvitale , Joshua C. Bufton , Fiona J. Sorrell , Nicolae Solcan , Rod Chalk , James Doutch , Alex N. Bullock Biochemical Journal DOI: 10.1042/BCJ20170527 Diamond Proposal Number(s): [8421] Show Abstract ▼ Abstract: Members of the potassium channel tetramerization domain (KCTD) family are soluble non-channel proteins that commonly function as Cullin3 (Cul3)-dependent E3 ligases. Solution studies of the N-terminal BTB domain have suggested that some KCTD family members may tetramerize similarly to the homologous tetramerization domain (T1) of the voltage-gated potassium (Kv) channels. However, available structures of KCTD1, KCTD5 and KCTD9 have demonstrated instead pentameric assemblies. To explore other phylogenetic clades within the KCTD family, we determined the crystal structures of the BTB domains of a further five human KCTD proteins revealing a rich variety of oligomerization architectures, including monomer (SHKBP1), a novel two-fold symmetric tetramer (KCTD10 and KCTD13), open pentamer (KCTD16) and closed pentamer (KCTD17). While these diverse geometries were confirmed by small-angle X-ray scattering (SAXS), only the pentameric forms were stable upon size-exclusion chromatography. With the exception of KCTD16, all proteins bound to Cul3 and were observed to reassemble in solution as 5:5 heterodecamers. SAXS data and structural modelling indicate that Cul3 may stabilize closed BTB pentamers by binding across their BTB-BTB interfaces. These extra interactions likely also allow KCTD proteins to bind Cul3 without the expected 3-box motif. Overall, these studies reveal the KCTD family BTB domain to be a highly versatile scaffold compatible with a range of oligomeric assemblies and geometries. This observed interface plasticity may support functional changes in regulation of this unusual E3 ligase family.	Sep 2017
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Family-wide Structural Analysis of Human Numb-Associated Protein Kinases Fiona Sorrell , Marta Szklarz , Kamal r Abdul azeez , Jon m Elkins , Stefan Knapp Structure DOI: 10.1016/j.str.2015.12.015 Diamond Proposal Number(s): [10619] Open Access Show Abstract ▼ Abstract: The highly diverse Numb-associated kinase (NAK) family has been linked to broad cellular functions including receptor-mediated endocytosis, Notch pathway modulation, osteoblast differentiation, and dendrite morphogenesis. Consequently, NAK kinases play a key role in a diverse range of diseases from Parkinson's and prostate cancer to HIV. Due to the plasticity of this kinase family, NAK kinases are often inhibited by approved or investigational drugs and have been associated with side effects, but they are also potential drug targets. The presence of cysteine residues in some NAK family members provides the possibility for selective targeting via covalent inhibition. Here we report the first high-resolution structures of kinases AAK1 and BIKE in complex with two drug candidates. The presented data allow a comprehensive structural characterization of the NAK kinase family and provide the basis for rational design of selective NAK inhibitors.	Feb 2016
I04-1-Macromolecular Crystallography (fixed wavelength)	Identification and Characterization of a Small-Molecule Inhibitor of Death-Associated Protein Kinase 1 Theis S. Wilbek , Tine Skovgaard , Fiona Sorrell , Stefan Knapp , Jens Berthelsen , Kristian Stromgaard ChemBioChem 16 (1), 59 - 63 DOI: 10.1002/cbic.201402512 PMID: 25382253 Diamond Proposal Number(s): [8421, 10619] Open Access Show Abstract ▼ Abstract: A novel imidazo-pyramidazine inhibitor of DAPK1 that undergoes class-specific interactions and extends into the substrate recognition site has been identified. This inhibitor is a good starting point for the development of selective and potent inhibitors of DAPK1, with potential use against stroke and ischemia.	Jan 2015
I02-Macromolecular Crystallography	Structural and biochemical characterization of the KLHL3WNK kinase interaction important in blood pressure regulation Frances-rose Schumacher , Fiona Sorrell , Dario r. Alessi , Alex n. Bullock , Thimo Kurz Biochemical Journal 460, 237 - 246 DOI: 10.1042/BJ20140153 PMID: 24641320 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: WNK1 [with no lysine (K)] and WNK4 regulate blood pressure by controlling the activity of ion co-transporters in the kidney. Groundbreaking work has revealed that the ubiquitylation and hence levels of WNK isoforms are controlled by a Cullin-RING E3 ubiquitin ligase complex (CRL3KLHL3) that utilizes CUL3 (Cullin3) and its substrate adaptor, KLHL3 (Kelch-like protein 3). Loss-of-function mutations in either CUL3 or KLHL3 cause the hereditary high blood pressure disease Gordon's syndrome by stabilizing WNK isoforms. KLHL3 binds to a highly conserved degron motif located within the C-terminal non-catalytic domain of WNK isoforms. This interaction is essential for ubiquitylation by CRL3KLHL3 and disease-causing mutations in WNK4 and KLHL3 exert their effects on blood pressure by disrupting this interaction. In the present study, we report on the crystal structure of the KLHL3 Kelch domain in complex with the WNK4 degron motif. This reveals an intricate web of interactions between conserved residues on the surface of the Kelch domain β-propeller and the WNK4 degron motif. Importantly, many of the disease-causing mutations inhibit binding by disrupting critical interface contacts. We also present the structure of the WNK4 degron motif in complex with KLHL2 that has also been reported to bind WNK4. This confirms that KLHL2 interacts with WNK kinases in a similar manner to KLHL3, but strikingly different to how another KLHL protein, KEAP1 (Kelch-like enoyl-CoA hydratase-associated protein 1), binds to its substrate NRF2 (nuclear factor-erythroid 2-related factor 2). The present study provides further insights into how Kelch-like adaptor proteins recognize their substrates and provides a structural basis for how mutations in WNK4 and KLHL3 lead to hypertension.	Jun 2014

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