A5071951722- Photoreceptor and optogenetics research
- Retinal Development and Disorders
- Receptor Mechanisms and Signaling
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Photosynthetic Processes and Mechanisms
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- CAR-T cell therapy research
- Peptidase Inhibition and Analysis
- Folate and B Vitamins Research
- bioluminescence and chemiluminescence research
- Lymphoma Diagnosis and Treatment
- Neuroscience and Neuropharmacology Research
- Iron oxide chemistry and applications
- Microbial Community Ecology and Physiology
- Click Chemistry and Applications
- Metabolism, Diabetes, and Cancer
- Marine and coastal ecosystems
- Heat shock proteins research
- Nicotinic Acetylcholine Receptors Study
- Amino Acid Enzymes and Metabolism
- Porphyrin Metabolism and Disorders
- Molecular spectroscopy and chirality
Paul Scherrer Institute
2022-2024
Institute of Cancer Research
2020-2024
University of Southampton
2017-2024
Diamond Light Source
2021-2024
Cancer Research UK
2020-2022
Abstract Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs) 1 . A photon absorbed 11- cis retinal chromophore rhodopsin, which isomerizes within 200 femtoseconds to all- trans conformation 2 , thereby initiating cellular signal transduction processes that ultimately lead vision. However, intramolecular mechanism photoactivated induces activation events inside remains experimentally unclear. Here we use ultrafast time-resolved crystallography at...
Deregulation of the transcriptional repressor BCL6 enables tumorigenesis germinal center B-cells, and hence has been proposed as a therapeutic target for treatment diffuse large B-cell lymphoma (DLBCL). Herein we report discovery series benzimidazolone inhibitors protein–protein interaction between its co-repressors. A subset these were found to cause rapid degradation BCL6, optimization pharmacokinetic properties led...
Calmodulin (CaM) regulates many ion channels to control calcium entry into cells, and mutations that alter this interaction are linked fatal diseases. The structural basis of CaM regulation remains largely unexplored. In retinal photoreceptors, binds the CNGB subunit cyclic nucleotide-gated (CNG) and, thereby, adjusts channel's Cyclic guanosine monophosphate (cGMP) sensitivity in response changes ambient light conditions. Here, we provide characterization for a CNG channel by using...
The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes generally encode two different types of FutA iron-binding proteins: periplasmic FutA2 ABC transporter subunits bind Fe(III), while cytosolic FutA1 binds Fe(II). Owing their small size and economized genome ecotypes typically possess single futA gene. How the encoded protein might Fe oxidation states was previously unknown. Here, we use...
To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent Val18. With no opportunities for strong polar interactions, focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration different sized rings, identified conformationally restricted core which optimally filled available space, leading potent BCL6 inhibitors. Through X-ray structure-guided...
Abstract Changes in structure and dynamics elicited by agonist ligand binding at the extracellular side of G protein coupled receptors (GPCRs) must be relayed to cytoplasmic receptors. To decipher role water‐mediated hydrogen‐bond networks this relay mechanism, we have developed graph‐based algorithms analysis methodologies applicable datasets static structures distinct GPCRs. For a reference dataset bovine rhodopsin solved same resolution, show that graph analyses capture internal...
We describe the optimization of modestly active starting points to potent inhibitors BCL6 by growing into a subpocket, which was occupied network five stably bound water molecules. Identifying required not only forming new interactions in subpocket but also perturbing productive, potency-increasing fashion while controlling physicochemical properties. achieved this goal sequential manner systematically probing pocket and network, ultimately achieving 100-fold improvement activity. The most...
Abstract Animal vision depends on opsins, a category of G protein-coupled receptor (GPCR) that achieves light sensitivity by covalent attachment to retinal. Typically binding as an inverse agonist in the 11-cis form, retinal photoisomerizes all-trans isomer and activates receptor, initiating downstream signaling cascades. Retinal bound bistable opsins isomerizes back state after absorption second photon, inactivating receptor. Bistable are essential for invertebrate non-visual perception...
Animal vision depends on opsins, a category of G protein-coupled receptor (GPCR) that achieves light sensitivity by covalent attachment to retinal. Typically binding as an inverse agonist, 11-cis retinal photoisomerizes the all-trans isomer and activates receptor, initiating downstream signaling cascades. Retinal bound bistable opsins isomerizes back state after absorption second photon, inactivating receptor. Bistable are essential for invertebrate nonvisual perception across animal...
ABSTRACT Heterotrimeric G proteins play a central role in cellular signaling, acting as switchable molecular regulators. Consequently, pharmacological agents to control protein activity are of utmost importance advance our understanding this signal transduction system. The natural depsipeptides FR900359 (FR) and YM-254890 (YM) two highly specific widely used inhibitors heterotrimeric Gq/11 proteins. These compounds have traditionally been understood inhibit GDP dissociation by preventing the...
Abstract By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for formation and maintenance germinal centres. As BCL6 deregulation is implicated in development Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt BCL6-corepressor protein–protein interaction (PPI). Here report our hit finding compound optimisation strategies, which provide...
Abstract Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs). A photon absorbed 11- cis retinal chromophore which isomerises within 200 femtoseconds to all- trans conformation, thereby initiating cellular signal transduction processes that ultimately lead vision. However, intramolecular mechanism photoactivated induces activation events inside remains elusive. In this work, we use ultrafast time-resolved crystallography at room temperature...
Abstract Opsins are G protein-coupled receptors (GPCRs) that have evolved to detect light stimuli and initiate intracellular signaling cascades. Their role as signal transducers is critical perception across the animal kingdom. covalently bind chromophore 11-cis retinal, which isomerizes all-trans isomer upon photon absorption, causing conformational changes result in receptor activation. Monostable opsins, responsible for vision vertebrates, release after activation must another retinal...
Opsins are G protein-coupled receptors (GPCRs) that have evolved to detect light stimuli and initiate intracellular signaling cascades. Their role as signal transducers is critical perception across the animal kingdom. covalently bind chromophore 11-cis retinal, which isomerizes all-trans isomer upon photon absorption, causing conformational changes result in receptor activation. Monostable opsins, responsible for vision vertebrates, release after activation must another retinal molecule...
Protein–inhibitor crystal structures aid medicinal chemists in efficiently improving the potency and selectivity of small-molecule inhibitors. It is estimated that a quarter lead molecules drug discovery projects are halogenated. have shed light on role halogen atoms ligand binding. They form bonds with protein improve shape complementarity inhibitors binding sites. However, specific radiation damage (SRD) can cause cleavage carbon–halogen (C– X ) during X-ray diffraction data collection....
Rhodopsin is a G-protein-coupled receptor that detects light and initiates the intracellular signalling cascades underpin vertebrate vision. Light sensitivity achieved by covalent linkage to 11- cis retinal, which isomerizes upon photo-absorption. Serial femtosecond crystallography data collected from rhodopsin microcrystals grown in lipidic cubic phase were used solve room-temperature structure of receptor. Although diffraction showed high completeness good consistency 1.8 Å resolution,...
The Pdx1 enzyme catalyses condensation of two carbohydrates and ammonia to form pyridoxal 5-phosphate (PLP) via an imine relay mechanism carbonyl intermediates. I333 intermediate characterised here using structural, UV-vis absorption spectroscopy mass spectrometry analyses rationalises stereoselective deprotonation subsequent substrate assisted phosphate elimination, central PLP biosynthesis.
Abstract The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes typically encode two different types of FutA binding proteins: periplasmic FutA2 ABC transporter subunits bind Fe(III), while cytosolic FutA1 binds Fe(II). Owing their small size and economized genome ecotypes possess single futA gene. How the encoded protein might Fe oxidation states was previously unknown. Here we use...