A5030970382- Advanced Breast Cancer Therapies
- HER2/EGFR in Cancer Research
- Cytokine Signaling Pathways and Interactions
- 14-3-3 protein interactions
- Ubiquitin and proteasome pathways
- Enzyme Structure and Function
- Cell Adhesion Molecules Research
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- Genomics and Rare Diseases
- Receptor Mechanisms and Signaling
- Blood properties and coagulation
- Protein Structure and Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Phosphodiesterase function and regulation
- Wnt/β-catenin signaling in development and cancer
- Hip disorders and treatments
- Shoulder Injury and Treatment
- Cancer Research and Treatments
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Musculoskeletal synovial abnormalities and treatments
- Cancer-related Molecular Pathways
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
University of Oxford
2017-2024
Central European Institute of Technology – Masaryk University
2024
Central European Institute of Technology
2024
Universidad Loyola Andalucía
2024
Genomics (United Kingdom)
2017-2020
ETH Zurich
2013-2020
Nuffield Health
2019
Genomics England
2018
Stanford University
2007-2012
Human transglutaminase 2 (TG2), a member of large family enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology many tissues and is implicated gluten-induced pathogenesis celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members this crystallized conformations with inaccessible active sites. We trapped human TG2 complex inhibitor mimics inflammatory gluten peptide...
Transglutaminase 2 (TG2) in the extracellular matrix is largely inactive but transiently activated upon certain types of inflammation and cell injury. The enzymatic activity TG2 thus appears to be tightly regulated. As known sensitive changes redox environment, inactivation through oxidation presents a plausible mechanism. Using mass spectrometry, we have identified redox-sensitive cysteine triad consisting Cys230, Cys370, Cys371 that involved oxidative TG2. Within this triad, Cys370 was...
The FAM83 proteins anchor various isoforms of the constitutively active kinase CK1 to specific subcellular locations.
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 N-terminal BTB have suggested some KCTD members may tetramerize similarly to homologous (T1) voltage-gated (Kv) channels. However, available structures KCTD1, KCTD5 and KCTD9 demonstrated instead pentameric assemblies. To explore other phylogenetic clades within family, we determined crystal domains a further...
encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.
Article19 July 2018Open Access Source DataTransparent process Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling Matous Hrdinka orcid.org/0000-0002-2981-2825 Nuffield Department Clinical Medicine, Ludwig Institute for Cancer Research, University Oxford, UK Search more papers by this author Lisa Schlicher Bing Dai Developmental, Molecular & Chemical Biology, Tufts School Boston, MA, USA Daniel M Pinkas Structural Genomics Consortium, Joshua C Bufton...
A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective discoidin domain receptor 1 (DDR1) inhibitors. One the representative compounds, 7f, bound with DDR1 a Kd value 5.9 nM suppressed kinase activity an half-maximal (50%) inhibitory concentration 14.9 nM. 7f potently inhibited collagen-induced signaling epithelial–mesenchymal transition, dose-dependently colony formation pancreatic cancer cells, exhibited promising in vivo therapeutic...
Discoidin-domain receptors 1 and 2 (DDR1 DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed optimized to coinhibit DDR1 DDR2. One the most promising compounds, 5n, tightly bound DDR2 proteins with Kd values 7.9 8.0 nM; potently inhibited kinases IC50 9.4 20.4 nM, respectively; was significantly less potent a panel 403 wild-type at 1.0 μM. DDR1- DDR2-kinase inhibition by 5n validated Western-blotting analysis in primary...
Abstract RA110 is a computationally designed retro‐aldolase enzyme that utilizes amine catalysis to convert 4‐hydroxy‐4‐(6‐methoxy‐2‐naphthyl)‐2‐butanone 6‐methoxy‐2‐naphthaldehyde and acetone. The original design accelerated substrate cleavage by factor of 12 000 over background, its activity was subsequently increased more than thousand‐fold directed evolution. X‐ray structure the evolved catalyst covalently modified with 1,3‐diketone inhibitor deviates substantially from model, however,...
Important reactions in biology and biocatalysis involve proton abstraction from carbon. When the resulting anionic charge is delocalized carbon to an oxygen atom, these deprotonations can be catalytically accelerated by oxyanion stabilization. Oxyanion stabilization a glutamine side chain (Gln50) was thought accelerate C–H HG3.17, computationally designed biocatalyst that had been evolutionarily optimized enzyme-like efficiency. We present kinetic data crystal structures at atomic resolution...
Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting activation loop might offer improved inhibitor selectivity since this region kinases is less conserved. However, strategy presents difficulties flexibility. Herein, we report design receptor-interacting protein 2 (RIPK2) based on pan-kinase regorafenib that aim engage basic residues Lys169 or Arg171. We...
Receptor-interacting protein kinase 2 (RIPK2) is a key mediator of nucleotide-binding oligomerization domain (NOD) cell signaling that has been implicated in various chronic inflammatory conditions. A new class RIPK2 kinase/NOD inhibitors based on 3,5-diphenyl-2-aminopyridine scaffold was developed. Several co-crystal structures RIPK2•inhibitor complexes were analyzed to provide insights into inhibitor selectivity versus the structurally related activin receptor-like (ALK2) demonstrating...
MICAL proteins play a crucial role in cellular dynamics by binding and disassembling actin filaments, impacting processes like axon guidance, cytokinesis, cell morphology. Their activity is tightly controlled, as dysregulation can lead to detrimental effects on Although previous studies have suggested that MICALs are autoinhibited, require Rab become active, the detailed molecular mechanisms remained unclear. Here, we report cryo-EM structure of human MICAL1 at nominal resolution 3.1 Å....
The functional and biological significance of selected CASP13 targets are described by the authors structures. structural biologists discuss most interesting features target proteins assess whether these were correctly reproduced in predictions submitted to experiment.
Adiponectin has many beneficial effects on cardiovascular and obesity-related disorders. It is part of a class proteins that contains short collagenous domains, along with surfactant A D, complement protein C1q. This biomacromolecules requires post-translational modifications to form biologically active assemblies. By introducing set modifying enzymes into Escherichia coli, we have created prokaryotic expression system functionally assembles adiponectin, as assessed by the ability produced...
KCTD family proteins typically assemble into cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in cause developmental abnormalities and kidney fibrosis scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of human KCTD1. Disease-causing mutation P20S maps to unrecognized extension BTB domain contributes both its pentameric TFAP2A binding. The C-terminal (CTD) shares fold assembly with...
Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal pulmonary fibrosis, atherosclerosis, various forms of cancer. Potent selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases the tyrosine protein receptor TIE or tropomyosin kinases, which are related angiogenesis neuronal toxicity. In this study, we optimized our...
SUMMARY KCTD family proteins typically assemble into Cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in cause developmental abnormalities and kidney fibrosis scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of full-length KCTD1. Disease-causing mutation P20S maps to unrecognized extension BTB domain contributes both its pentameric TFAP2A binding. The C-terminal (CTD) shares fold...