A5085891527- Fibroblast Growth Factor Research
- Magnetic confinement fusion research
- Eosinophilic Disorders and Syndromes
- Advanced Electron Microscopy Techniques and Applications
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- HIV/AIDS drug development and treatment
- ATP Synthase and ATPases Research
- Chemical Synthesis and Analysis
- Superconducting Materials and Applications
- HIV Research and Treatment
- Click Chemistry and Applications
- Helicobacter pylori-related gastroenterology studies
- Kruppel-like factors research
- Estrogen and related hormone effects
- Mast cells and histamine
- Protein Kinase Regulation and GTPase Signaling
- Monoclonal and Polyclonal Antibodies Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Electric Motor Design and Analysis
- Particle accelerators and beam dynamics
- Photosynthetic Processes and Mechanisms
- Induction Heating and Inverter Technology
- RNA and protein synthesis mechanisms
AstraZeneca (United Kingdom)
2014-2023
Pfizer (United Kingdom)
2005-2016
AstraZeneca (Brazil)
2016
Pfizer (United States)
2005-2014
Kansas State University
2005
Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe design a series novel stapled coactivator peptide site estrogen receptors. Using number biophysical techniques, including crystal structure analysis receptor-stapled complexes, in detail molecular interactions demonstrate all-hydrocarbon staples modulate recognition events. The findings...
// Harshnira Patani 1, * , Tom D. Bunney Nethaji Thiyagarajan 1 Richard A. Norman 2 Derek Ogg Jason Breed Paul Ashford Andrew Potterton Mina Edwards Sarah V. Williams 3 Gary S. Thomson 4 Camilla S.M. Pang Margaret Knowles Alexander L. Breeze Christine Orengo Chris Phillips Matilda Katan Institute of Structural and Molecular Biology, Division Biosciences, University College London, Gower St, London WC1E 6BT, UK Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire...
Cryoelectron microscopy (Cryo-EM) has enabled structural determination of proteins larger than about 50 kDa, including many intractable by any other method, but it largely failed for smaller proteins. Here, we obtain structures small binding them to a rigid molecular scaffold based on designed protein cage, revealing atomic details at resolutions reaching 2.9 Å. We apply this system the key cancer signaling KRAS (19 kDa in size), obtaining four oncogenic mutational variants cryo-EM....
Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization the stomach, this Gram-negative bacterium adheres to Lewis(b) (Le(b)) antigens in mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, thus, molecular mechanism recognizing Le(b) remains unknown. We present crystal structure extracellular domain BabA, from H. strain J99, absence presence at 2.0- 2.1-Å resolutions, respectively....
Abstract Protein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp–Phe–Gly (DFG) motif activation loop, with some, including FGFR1 kinase, appearing refractory this so-called ‘DFG flip’. Recent inhibitor-bound structures have unexpectedly revealed for first time a ‘DFG-out’ state. Here we use conformationally selective inhibitors as chemical probes interrogation structural and dynamic features that appear govern DFG flip FGFR1. Our detailed...
Pyruvate dehydrogenase kinase (PDHK) regulates the activity of pyruvate multienzyme complex. PDHK inhibition provides a route for therapeutic intervention in diabetes and cardiovascular disorders. We report crystal structures human isozyme 2 complexed with physiological synthetic ligands. Several PDHK2 disclosed have C-terminal cross arms that span large trough region between N-terminal regulatory (R) domains dimers. The containing bound ATP ADP demonstrate variation conformation active site...
A systematic thermodynamic analysis of benzene sulfonamide derivatives binding to carbonic anhydrase revealed a unique change in enthalpy for one the compounds investigated. Subsequent X-ray showed different mode this compound and further optimization led high-affinity, enthalpy-driven compound, emphasizing importance profiling. Detailed facts specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available...
The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment human immunodeficiency virus type 1 (HIV-1). A major problem with first approved NNRTIs was emergence mutations in HIV-1 (RT), particular K103N and Y181C, which led to resistance entire class. We adopted an iterative strategy synthesize test small molecule from a chemical series pyrazoles against wild-type (wt) RT most prevalent NNRTI-resistant...
Abstract MLK4 is a member of the mixed-lineage family kinases that regulate JNK, p38, and ERK kinase signaling pathways. mutations have been identified in various human cancers, including frequently colorectal cancer, where their function pathobiological importance uncertain. In this study, we assessed functional consequences colon tumorigenesis. Biochemical data indicated majority are loss-of-function (LOF) can exert dominant-negative effects. seeking to understand abrogated activity these...
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack resilience to mutations in (RT) enzyme. Using structural overlays known efavirenz and capravirine complexed RT as a starting point, structure-based drug design techniques, we have created novel series indazole NNRTIs that possess excellent metabolic stability mutant resilience.
The authors have used a surface plasmon resonance (SPR)-based biosensor approach to identify and characterize compounds with unique binding mode protein kinases. Biacore was hits from an enzymatic high-throughput screen of the Tec family tyrosine kinase, IL2-inducible T cell kinase (ITK). Complex kinetics observed for some compounds, which led identification that bound simultaneously at both adenosine triphosphate (ATP) site second, allosteric on ITK. presence second confirmed by X-ray...
ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has well-validated role their proliferation, cytokine release chemotaxis. an attractive target for the treatment T-cell-mediated inflammatory diseases. In present study we describe discovery kinase inhibitors that preferentially bind to allosteric pocket ITK. The novel site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology X-ray...
MAP kinases act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such proliferation, differentiation, regulation transcription development. As member the kinase family, ERK5 (MAPK7) is downstream signalling pathways various cell-surface receptors, including receptor tyrosine G protein-coupled receptors. In current study, five structures domain co-crystallized with inhibitors reported. Interestingly, three compounds bind at...
Spleen tyrosine kinase is a non-receptor kinase, overactivation of which thought to contribute autoimmune diseases as well allergy and asthma. Protein kinases have highly conserved ATP binding site, thus making challenging the design selective small molecule inhibitors. It has been documented that some protein can be stabilized in their inactive conformations (Type-II inhibitors). Herein, we describe structure/ligand-based approach successfully identify ligands bind novel spleen kinase. By...
Abstract Numerous technical advances have made cryo-EM an attractive method for atomic structure determination. Cryo-EM is ideally suited large macromolecular structures, while problems of low signal-to-noise prevent routine determination proteins smaller than about 50 kDa. This size limitation excludes numbers important cellular from structural characterization by this powerful technique, including many cell-signaling high therapeutic interest. In the present work, we use molecular...
CYP 2C9 co-crystal structures of compound<bold>1</bold>(green) in binding mode 1 (CYP green) and compound<bold>2</bold>(yellow) 2 yellow).