Discovery and development of an oral analgesic targeting the α2B adrenoceptor.

Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an α2A-adrenergic receptor. Hence, α2-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension/hypotension and bradycardia.

Advancing Compatibility and Interfacial Interaction Between PEEK and GNPs Through a Strategic Approach Using Pyrene-Functionalized PDMAEMA-b-PMMA Copolymer.

Polyetheretherketone (PEEK), known for its high heat and chemical resistance and excellent mechanical properties, is extensively utilized, particularly as a metal substitute, in the automotive industry. Although PEEK exhibits outstanding properties, enhancements are essential to improve its practical performance. In this study, we aimed to improve the performance of PEEK by incorporating graphene nanoplatelets (GNPs) and optimizing their dispersion through non-covalent functionalization.

Structural basis for the subtype-selectivity of K2.2 channel activators.

Small-conductance (K2.2) and intermediate-conductance (K3.1) Ca-activated K channels are gated by a Ca-calmodulin dependent mechanism.

Cryo-EM structures of the small-conductance Ca-activated K2.2 channel.

Small-conductance Ca-activated K (K2.1-K2.3) channels modulate neuronal and cardiac excitability.

The structure and function of the ghrelin receptor coding for drug actions.

Drugs targeting the ghrelin receptor hold therapeutic potential in anorexia, obesity and diabetes. However, developing effective drugs is challenging. To tackle this common issue across a broad drug target, this study aims to understand how anamorelin, the only approved drug targeting the ghrelin receptor, operates compared to other synthetic drugs.

Neurotransmitter recognition by human vesicular monoamine transporter 2.

Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear.

Crystal structure reveals the binding mode and selectivity of a photoswitchable ligand for the adenosine A receptor.

Rational synthetic expansion of photoresponsive ligands is important for photopharmacological studies. Adenosine A receptor (AR) is stimulated by adenosine and related in Parkinson's disease and other diseases. Here, we report the crystal structure of the AR in complex with the novel photoresponsive ligand photoNECA (blue) at 3.

Structural insights into the agonists binding and receptor selectivity of human histamine H receptor.

Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H receptor (HR) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the HR-G complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket.

Mapping protein dynamics at high spatial resolution with temperature-jump X-ray crystallography.

Understanding and controlling protein motion at atomic resolution is a hallmark challenge for structural biologists and protein engineers because conformational dynamics are essential for complex functions such as enzyme catalysis and allosteric regulation. Time-resolved crystallography offers a window into protein motions, yet without a universal perturbation to initiate conformational changes the method has been limited in scope. Here we couple a solvent-based temperature jump with time-resolved crystallography to visualize structural motions in lysozyme, a dynamic enzyme.

Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor.

Orexin receptors are a family of G protein-coupled receptors that consist of two subtypes: orexin-1 receptors (OX1Rs) and OX2Rs. They are expressed throughout the central nervous system and are involved in regulating the sleep-wake cycle. The development of antagonists to orexin receptors has become important in drug discovery because modulation of these receptors can lead to novel treatments for diseases related to the regulation of sleep and wakefulness, such as insomnia.

S1PR3-G-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation.

Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis).

Structure of the dopamine D receptor in complex with the antipsychotic drug spiperone.

In addition to the serotonin 5-HT receptor (5-HTR), the dopamine D receptor (DR) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of DR have been described in complex with the inverse agonists risperidone (DR) and haloperidol (DR). Here we describe the structure of human DR in complex with spiperone (DR).

Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals.

Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments.

The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone.

Angiotensin II (AngII) is a peptide hormone that plays a key role in regulating blood pressure, and its interactions with the G protein-coupled receptors, AngII type-1 receptor (ATR) and AngII type-2 receptor (ATR), are central to its mechanism of action. We solved the crystal structure of human ATR bound to AngII and its specific antibody at 3.2-Å resolution.

Structures of the 5-HT receptor in complex with the antipsychotics risperidone and zotepine.

Many drugs target the serotonin 2A receptor (5-HTR), including second-generation antipsychotics that also target the dopamine D receptor (DR). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HTR in complex with the second-generation antipsychotics risperidone and zotepine.

Ligand complex structures of l-amino acid oxidase/monooxygenase from sp. AIU 813 and its conformational change.

Unlabelled: l-Amino acid oxidase/monooxygenase from sp. AIU 813 (l-AAO/MOG) catalyzes both the oxidative deamination and oxidative decarboxylation of the α-group of l-Lys to produce a keto acid and amide, respectively. l-AAO/MOG exhibits limited specificity for l-amino acid substrates with a basic side chain.

Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA.

Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-Å and 1.

A three-dimensional movie of structural changes in bacteriorhodopsin.

Bacteriorhodopsin (bR) is a light-driven proton pump and a model membrane transport protein. We used time-resolved serial femtosecond crystallography at an x-ray free electron laser to visualize conformational changes in bR from nanoseconds to milliseconds following photoactivation. An initially twisted retinal chromophore displaces a conserved tryptophan residue of transmembrane helix F on the cytoplasmic side of the protein while dislodging a key water molecule on the extracellular side.

Mutational and crystallographic analysis of l-amino acid oxidase/monooxygenase from Pseudomonas sp. AIU 813: Interconversion between oxidase and monooxygenase activities.

In this study, it was shown for the first time that l-amino acid oxidase of Pseudomonas sp. AIU813, renamed as l-amino acid oxidase/monooxygenase (l-AAO/MOG), exhibits l-lysine 2-monooxygenase as well as oxidase activity. l-Lysine oxidase activity of l-AAO/MOG was increased in a p-chloromercuribenzoate (p-CMB) concentration-dependent manner to a final level that was five fold higher than that of the non-treated enzyme.

Crystal structures of glycoside hydrolase family 51 α-L-arabinofuranosidase from Thermotoga maritima.

α-L-Arabinofuranosidase from the hyperthermophilic bacterium Thermotoga maritima (Tm-AFase) is an extremely thermophilic enzyme belonging to glycoside hydrolase family 51. It can catalyze the transglycosylation of a novel glycosyl donor, 4,6-dimethoxy-1,3,5-triazin-2-yl (DMT)-β-D-xylopyranoside. In this study we determined the crystal structures of Tm-AFase in substrate-free and complex forms with arabinose and xylose at 1.