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| Open AccessInhibition of NMDA receptors through a membrane-to-channel path
Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.
- Madeleine R. Wilcox
- , Aparna Nigam
- & Jon W. Johnson
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Article
| Open AccessPeripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects
The current peripherally acting mu-opioid receptor antagonists present limited permeability and pharmacokinetic properties. Here, the authors develop a drug delivery approach based on AG10, which demonstrates the impact of mu-opioid receptors in the central nervous system in precipitating opioid-induced constipation.
- Md Tariqul Haque Tuhin
- , Dengpan Liang
- & Mamoun M. Alhamadsheh
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Article
| Open AccessCoordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue
Cell-type-specific activation of receptors is desirable for elucidating their roles in tissues or animals. Here, the authors developed a chemogenetic method for direct activation of mGlu1, a GPCR-type glutamate receptor subtype, and demonstrate its use in mouse brain tissue.
- Kento Ojima
- , Wataru Kakegawa
- & Shigeki Kiyonaka
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Article
| Open AccessPI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling
Fatty acid unsaturation by stearoyl-CoA desaturase 1 (SCD1) protects against cellular stress through unclear mechanisms. Here the authors show 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) is an SCD1-derived signaling lipid that regulates stress-adaption, protects against cell death and promotes proliferation.
- Maria Thürmer
- , André Gollowitzer
- & Andreas Koeberle
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Article
| Open AccessMolecular mechanism of the wake-promoting agent TAK-925
The OX2 orexin receptor (OX2R) is a brain GPCR that regulates wakefulness and circadian rhythms in humans, and a potential drug target in insomnia and narcolepsy. Here, the authors use cryo-EM to determine how the first clinically tested OX2R agonist TAK-925 can activate OX2R in a selective manner.
- Jie Yin
- , Yanyong Kang
- & Daniel M. Rosenbaum
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Article
| Open AccessA genetic engineering strategy for editing near-infrared-II fluorophores
It is currently difficult to synthesise NIR-II probes with good quantum yields, biocompatibility and pharmacokinetics. Here the authors report a strategy to alter these properties by modifying the protein coatings with biofunctional molecules, and generate long-wavelength fluorophores for in vivo imaging.
- Rui Tian
- , Xin Feng
- & Xiaoyuan Chen
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Article
| Open AccessStructural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
KATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic KATP in both the closed state and the pre-open state. These structures illuminate the mechanism of KATP channel regulation by the intracellular nucleotides.
- Mengmeng Wang
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessThe pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites
G-protein-coupled receptors bind endogenous ligands at sites that are frequently highly conserved. Here, authors computationally describe alternative allosteric pockets, several of which have not been targeted by synthetic ligands before.
- Janik B. Hedderich
- , Margherita Persechino
- & Peter Kolb
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Article
| Open AccessMolecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Acquired drug resistance is common during chemotherapy. Here, the authors describe the structural basis and molecular mechanism by which allosteric and clinically approved, ATP-competitive inhibitors of EGFR synergize to overcome resistance in lung cancer.
- Tyler S. Beyett
- , Ciric To
- & Michael J. Eck
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Article
| Open AccessThe dopamine transporter antiports potassium to increase the uptake of dopamine
The dopamine transporter, DAT, controls dopamine signaling by facilitating its reuptake using the Na+ gradient as driving force. Here, the authors uncover that an antiport of K+ ions also contributes to setting the rate of DAT-mediated dopamine clearance.
- Solveig G. Schmidt
- , Mette Galsgaard Malle
- & Claus J. Loland
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Article
| Open AccessIndisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.
- Anke Nijhuis
- , Arti Sikka
- & Hector C. Keun
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Article
| Open AccessAn orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion
Huntington’s disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.
- Caroline Gubser Keller
- , Youngah Shin
- & Rajeev Sivasankaran
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Article
| Open AccessStructural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors
Multi-targeting agonists at GIPR, GLP-1R or GCGR are pursued vigorously. Here, the authors report cryo-EM structures of tirzepatide-bound GIPR and GLP-1R, peptide 20-bound GIPR, GLP-1R and GCGR, revealing the molecular basis of their multiplexed pharmacological actions.
- Fenghui Zhao
- , Qingtong Zhou
- & Ming-Wei Wang
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Article
| Open AccessFunctionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists
Insulin therapies for patients with diabetes have challenges, including diminished hepatic preference of insulin action compared with endogenous insulin. Here the authors characterize insulin dimers that function as insulin receptor partial agonists, and exhibit hepatic and adipose tissue preference of insulin action and metabolic benefits in preclinical models.
- Margaret Wu
- , Ester Carballo-Jane
- & James Mu
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Article
| Open AccessCryo-EM structures of human bradykinin receptor-Gq proteins complexes
Type 2 bradykinin receptor (B2R) is essential in vasodilation and cardioprotection. Here the authors present two cryo-EM structures of human B2R-Gq in complex with bradykinin and kallidin to elucidate the mechanisms for ligand binding, receptor activation, and Gq proteins coupling.
- Jinkang Shen
- , Dongqi Zhang
- & Haitao Zhang
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Article
| Open AccessLung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.
- Barbara Spix
- , Elisabeth S. Butz
- & Christian Grimm
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Article
| Open AccessDynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.
- Giuseppe Deganutti
- , Yi-Lynn Liang
- & Denise Wootten
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Article
| Open AccessMaximizing response to intratumoral immunotherapy in mice by tuning local retention
Understanding the pharmacokinetics of locally-injected drugs could aid in the design of immunotherapies to maximize their therapeutic effect. Here, by evaluating different IL-2 fusion proteins, the authors show that molecular weight and matrix binding affect anti-tumor immune response and report a pharmacokinetic framework to predict response to intratumoral IL-2 therapy.
- Noor Momin
- , Joseph R. Palmeri
- & K. Dane Wittrup
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| Open AccessParacrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects
Fibroblast growth factors are involved in systemic glucose homeostasis and of interest for developing therapies for type 2 diabetes and associated metabolic diseases. Here the authors identify paracrine FGF4 as an anti-hyperglycemic FGF, which targets skeletal muscle to upregulate the glucose transporter GLUT4 cell surface abundance.
- Lei Ying
- , Luyao Wang
- & Zhifeng Huang
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Article
| Open AccessPharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells
The authors introduce PharmacoSTORM single-molecule imaging that uses fluorescent ligands and immunolabeling for cellular and subcellular nanoscale molecular pharmacology. They demonstrate its capabilities by visualizing cariprazine binding to D3 dopamine receptors on Islands of Calleja granule cell axons.
- Susanne Prokop
- , Péter Ábrányi-Balogh
- & István Katona
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Article
| Open AccessPreclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.
- Britton Boras
- , Rhys M. Jones
- & Charlotte Allerton
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Article
| Open AccessThe antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter
Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.
- Per Plenge
- , Dongxue Yang
- & Claus J. Loland
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Article
| Open AccessSelective targeting of ligand-dependent and -independent signaling by GPCR conformation-specific anti-US28 intrabodies
Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor.
- Timo W. M. De Groof
- , Nick D. Bergkamp
- & Martine J. Smit
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Article
| Open AccessRoutine sub-2.5 Å cryo-EM structure determination of GPCRs
There is a need to optimise cryo-EM data acquisition approaches to improve the resolution of GPCR cryo-EM structures to better than 2.5 Å, in order to use them for structure-based drug design purposes. Here, the authors present a systematic analysis of the main cryo-EM experimental parameters using three GPCRs as test cases, which is also of interest for the cryo-EM structure determination of other small membrane proteins.
- Radostin Danev
- , Matthew Belousoff
- & Patrick M. Sexton
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Article
| Open AccessA novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke
Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.
- Toshiko Yamazawa
- , Takuya Kobayashi
- & Takashi Murayama
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Article
| Open AccessNUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.
- Rina Nishii
- , Takanori Mizuno
- & Jun J. Yang
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Article
| Open AccessSite selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy
Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.
- Srijita Bhowmik
- , Juraj Galeta
- & Dalibor Sames
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Article
| Open AccessMolecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric Gs which offers insights into the molecular details of ago-allosterism.
- Zhaotong Cong
- , Li-Nan Chen
- & Ming-Wei Wang
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Article
| Open AccessCrystal structure of dopamine D1 receptor in complex with G protein and a non-catechol agonist
Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R.
- Bingfa Sun
- , Dan Feng
- & Brian K. Kobilka
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Article
| Open AccessZinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle
Metals such as calcium and potassium have long been known to regulate the diameter of arteries that control blood flow. Here, we report that zinc causes relaxation of blood vessels and reduces blood pressure by its coordinated action in sensory nerves, endothelium and smooth muscle cells.
- Ashenafi H. Betrie
- , James A. Brock
- & Scott Ayton
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Article
| Open AccessReversible modulation of circadian time with chronophotopharmacology
The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.
- Dušan Kolarski
- , Carla Miró-Vinyals
- & Ben L. Feringa
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Article
| Open AccessmRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease
Glycogen Storage Disease 1a (Gsd1a) is an inherited disorder caused by glucose 6-phosphatase (G6Pase-α) deficiency and characterized by hypoglycaemia and high risk of liver cancer. Here the authors develop a mRNA-based G6Pase-α delivery therapy that is efficacious and safe in a mouse model of GSD1a.
- Jingsong Cao
- , Minjung Choi
- & Paloma H. Giangrande
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Article
| Open AccessSLPI is a critical mediator that controls PTH-induced bone formation
The mechanism by which parathyroid hormone mediates the switch from bone resorption to bone formation is unclear. Here, the authors show that SLPI regulates the communication between osteoblasts and osteoclasts to promote the anabolic effect of parathyroid hormone.
- Akito Morimoto
- , Junichi Kikuta
- & Masaru Ishii
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Article
| Open AccessMachine learning identifies candidates for drug repurposing in Alzheimer’s disease
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.
- Steve Rodriguez
- , Clemens Hug
- & Artem Sokolov
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Article
| Open AccessStructural basis for ligand recognition of the neuropeptide Y Y2 receptor
The human neuropeptide Y receptor Y2 (Y2R) is a drug target for the treatment of obesity and anxiety. Crystal structure of Y2R bound to a selective antagonist and accompanying mutagenesis provide insights into ligand recognition and subtype specificity of NPY receptors.
- Tingting Tang
- , Christin Hartig
- & Beili Wu
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Article
| Open AccessAdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis
Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.
- Hongjiao Xu
- , Qian Zhao
- & Xianxing Jiang
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Article
| Open AccessDual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Propionic acidemia is a serious pediatric inherited disorder with no effective treatments. Here the authors demonstrate that delivering dual mRNAs as an enzyme replacement approach can be used as an effective therapy in a mouse model of propionic acidemia, with potential applicability to chronically administer multiple mRNAs in other genetic disorders.
- Lei Jiang
- , Ji-Sun Park
- & Lin T. Guey
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Article
| Open AccessChronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism
Both agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lead to weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Here the authors show that this may be explained by desensitization of GIPR activity by chronic GIPR agonism in vitro and in vivo.
- Elizabeth A. Killion
- , Michelle Chen
- & David J. Lloyd
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Article
| Open AccessGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
Growth hormone (GH) is a major modulator of physical growth and metabolism that is under tight regulatory control. Here the authors describe the signaling profile of GPR101, an orphan receptor that enhances GH secretion principally via constitutively activated Gs-PKA and Gq/11-PKC pathways.
- Dayana Abboud
- , Adrian F. Daly
- & Julien Hanson
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Article
| Open AccessTranslational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.
- Alison E. John
- , Rebecca H. Graves
- & Robert J. Slack
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Article
| Open AccessQuantifying CDK inhibitor selectivity in live cells
Cyclin-dependent kinase (CDK) inhibitors are widely used both in the clinic and for basic research aimed at dissecting the specific cellular functions of specific CDKs. Here, the authors report the development of a panel of fluorescent reporter probes and provide a comprehensive profile of the inhibitory activity of several CDK inhibitors towards all 21 CDKs in living cells.
- Carrow I. Wells
- , James D. Vasta
- & Matthew B. Robers
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Article
| Open AccessDietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion
The gut microbiota can alter the effects of anticancer fluoropyrimidines such as 5-fluorodeoxyuridine (FUdR) in the model organism C. elegans. Here, the authors show that these effects are further affected by diet, and dietary thymidine and serine increase FUdR toxicity in C. elegans via different mechanisms.
- Wenfan Ke
- , James A. Saba
- & Eyleen J. O’Rourke
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Article
| Open AccessImproved GPCR ligands from nanobody tethering
Antibodies conjugated to bioactive compounds can allow targeted delivery of therapeutics. Here the authors present a strategy for fusing nanobodies to suboptimal GPCR peptide ligands to potently and selectively activate receptors.
- Ross W. Cheloha
- , Fabian A. Fischer
- & Hidde L. Ploegh
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Article
| Open AccessInterference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.
- Angela Tomasovic
- , Theresa Brand
- & Kristina Lorenz
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Article
| Open AccessHaloperidol bound D2 dopamine receptor structure inspired the discovery of subtype selective ligands
The D2 dopamine receptor (DRD2) is one of the most well-established therapeutic targets for neuropsychiatric and endocrine disorders. Here, the authors report the crystal structure of the antipsychotic drug haloperidol bound to DRD2 via an extended binding pocket that distinguishes it from other D2-like subtypes.
- Luyu Fan
- , Liang Tan
- & Sheng Wang
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Article
| Open AccessChaperone mediated detection of small molecule target binding in cells
Quantitative profiling of small molecule-protein binding in cells can aid basic biochemical research and drug discovery. Here, the authors develop the Heat Shock Protein Inhibition Protein Stability Assay (HIPStA) as a high-throughput method to assess cellular target engagement and identify new drug targets.
- Kelvin F. Cho
- , Taylur P. Ma
- & Robert A. Blake
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Article
| Open AccessStructural insight into small molecule action on Frizzleds
WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, tissue homeostasis and human disease but no small molecule drugs targeting FZD with distinct efficacy have emerged so far. Here, authors identify the Smoothened agonist SAG1.3 as a partial agonist for FZD6 with limited subtype selectivity.
- Paweł Kozielewicz
- , Ainoleena Turku
- & Gunnar Schulte
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Article
| Open AccessEdible unclonable functions
Counterfeit medicines are a threat to patient health and public safety. Here, the authors use random patterns formed by fluorescent silk microparticles with various excitation and emission pairs as an edible physical unclonable function that can directly be attached onto the surface of medicines.
- Jung Woo Leem
- , Min Seok Kim
- & Young L. Kim
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Article
| Open AccessSUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis
FXR agonists have been investigated for the treatment of non-alcoholic steatohepatitis and liver fibrosis but the clinical efficacy is not optimal. Here the authors show that enhanced FXR SUMOylation in activated hepatic stellate cells reduces FXR signaling and that this can be rescued by SUMOylation inhibitors.
- Jiyu Zhou
- , Shuang Cui
- & Haiping Hao