A5055131583- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Pharmacological Effects and Assays
- Photosynthetic Processes and Mechanisms
- Photoreceptor and optogenetics research
- Mass Spectrometry Techniques and Applications
- Adenosine and Purinergic Signaling
- Chemical Reactions and Isotopes
- Neuroscience and Neuropharmacology Research
- Mitochondrial Function and Pathology
- Adipose Tissue and Metabolism
- Hormonal Regulation and Hypertension
- Protein Kinase Regulation and GTPase Signaling
- Pharmacological Receptor Mechanisms and Effects
- Monoclonal and Polyclonal Antibodies Research
- Lipid Membrane Structure and Behavior
- Fullerene Chemistry and Applications
- Enzyme Structure and Function
- Hemoglobin structure and function
- Alcohol Consumption and Health Effects
- Porphyrin Metabolism and Disorders
- Drug Transport and Resistance Mechanisms
- ATP Synthase and ATPases Research
- Analytical Chemistry and Sensors
- Spectroscopy and Quantum Chemical Studies
MRC Laboratory of Molecular Biology
2012-2024
Medical Research Council
2011-2019
High Energy Accelerator Research Organization
2015
Queen's Medical Centre
2015
University of Nottingham
2015
Heptares Therapeutics (United Kingdom)
2015
European Molecular Biology Laboratory
1992-2001
European Molecular Biology Laboratory
1994-2001
Tata Institute of Fundamental Research
2001
University of Helsinki
1998
The β1-adrenoceptor (β1AR) is the site of action beta blockers used in treatment cardiac-related illnesses. Two blockers, carvedilol and bucindolol, show distinctive activities compared to other have been proposed as treatments tailored Arg/Gly3898.56 polymorphism human β1AR. Both bucindolol are classified biased agonists, because they stimulate G protein-independent signaling, while acting either inverse or partial agonists protein pathway. We determined crystal structures a...
The β(1)-adrenergic receptor (β(1)AR) is a G-protein-coupled whose inactive state structure was determined using thermostabilized mutant (β(1)AR-M23). However, it not thought to be in fully inactivated because there no salt bridge between Arg139 and Glu285 linking the cytoplasmic ends of transmembrane helices 3 6 (the R(3.50) - D/E(6.30) "ionic lock"). Here we compare eight new structures β(1)AR-M23, from crystallographically independent molecules four different crystals with three...
The β1-adrenoceptor (β1AR) is a G protein-coupled receptor (GPCR) that activated by the endogenous agonists adrenaline and noradrenaline. We have determined structure of an ultra-thermostable β1AR mutant bound to weak partial agonist cyanopindolol 2.1 Å resolution. High-quality crystals (100 μm plates) were grown in lipidic cubic phase without assistance T4 lysozyme or BRIL fusion cytoplasmic loop 3, which commonly employed for GPCR crystallisation. An intramembrane Na+ ion was identified...
Biophysical fragment screening of a thermostabilized β1-adrenergic receptor (β1AR) using surface plasmon resonance (SPR) enabled the identification moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed activity chemotype, structure-based design approach protein-ligand crystal structures β1AR resulted in several fragments that bound with higher including indole 19 quinoline 20. In first example GPCR crystallography ligands...
G protein-coupled receptors (GPCRs) in the active state have higher affinity for agonists as compared with when they are inactive state, but molecular basis this is unclear. We determined four active-state structures of β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies presence varying efficacy. Comparison inactive-state β1AR identical ligands showed a 24 42% reduction volume orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up 30% increase...
Abstract A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., G s and β-arrestin. Using 13 C methyl methionine NMR for the β 1 -adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive pre-active state and, in with -mimetic nanobody, more less active ternary complexes. Formation of a basal activity through ligand-free nanobody–receptor interaction reveals structural...
A novel, improved method for purification of nitric oxide reductase (NOR) from membranes Paracoccus denitrificans has been developed. The purified enzyme is a cytochrome bc complex which, according to protein chemical and hydrodynamic data, contains two subunits in 1:1 stoichiometry. NorBC binds 0.87 g dodecyl maltoside/g forms dimer solution. Similarly, it dimeric two-dimensional crystals. Images these crystals have processed at 8 Å resolution projection the membrane. NorB subunit...
We previously found that the soxABCD operon encodes a quinol oxidase complex in Sulfolobus acidocaldarius and this enzyme was purified characterized. In study, we have used cloning procedure based on conservation of sequences polymerase chain reaction to isolate new gene ( soxM ) encoding subunit another terminal oxidase. This is fusion between two central components cytochrome oxidases, subunits I III. forms transcriptional unit which expressed under heterotrophic growth conditions. The...
Summary In Paracoccusdenitrificans the aa 3 ‐type cytochrome c oxidase and bb quinol have previously been characterized in detail, both biochemically genetically. Here we report on isolation of a genomic locus that harbours gene cluster ccoNOQP , demonstrate it encodes an alternative cbb oxidase. This has shown to be specifically induced at low oxygen tensions, suggesting its expression is controlled by oxygen‐sensing mechanism. view corroborated observation preceded FNR homologue promoter...
Summary A respiratory quinol oxidase complex that is encoded by the soxABCD operon has been purified from thermoacidophilic archaeon Sulfolobus acidocaldarius. The enzyme was solubilized with dodecyl maltoside and in presence of this detergent ethylene glycol. hydro‐dynamically homogeneous contains at least five different polypeptides. In addition to major subunits SoxA, SoxB SoxC, it two small One these translation product a short open reading frame (now called soxD gene) end operon....
Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial or weak agonists led proposal that rotamer changes Ser(5.46), coupled a contraction binding pocket, are sufficient increase probability activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is agonist β1AR and, based on hypothesis above, we predicted addition methyl group form...