Jens Carlsson

Jens Carlsson
Stockholm University | SU · Department of Biochemistry and Biophysics

About

89
Publications
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3,071
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Publications

Publications (89)
Article
Full-text available
The adenosine A 2A receptor (A 2A R), dopamine D 2 receptor (D 2 R) and metabotropic glutamate receptor type 5 (mGluR 5 ) form A 2A R-D 2 R-mGluR 5 heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the A 2A R protomer plays a major role in the inhibitory...
Article
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Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-bas...
Article
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Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the...
Article
Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Herein, we explored strategies for structure-based evolution of fragments binding to a G protein-coupled receptor. Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligand...
Article
Full-text available
G protein–coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome and are important therapeutic targets. During the last decade, the number of atomic-resolution structures of GPCRs has increased rapidly, providing insights into drug binding at the molecular level. These breakthroughs have created excitement...
Article
Structure-based docking screens of large compound libraries have become common in early drug and probe discovery. As computer efficiency has improved and compound libraries have grown, the ability to screen hundreds of millions, and even billions, of compounds has become feasible for modest-sized computer clusters. This allows the rapid and cost-ef...
Article
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The determination of G protein-coupled receptor (GPCR) structures at atomic resolution has improved understanding of cellular signaling and will accelerate the development of new drug candidates. However, experimental structures still remain unavailable for a majority of the GPCR family. GPCR structures and their interactions with ligands can also...
Article
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Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi‐target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the CNS. Here, a structure‐based strategy to identify dual‐target ligands of G prot...
Article
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Structure-based modelling was used to design a single compound with the ability to modulate the activity of two G-protein-coupled receptors relevant for Parkinson's disease. The most potent scaffold displayed nanomolar binding affinities for both targets and was active in a rat model of parkinsonism. Abstract Many diseases are polygenic and can on...
Article
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Ligand binding stabilizes different G protein-coupled receptor states via a complex allosteric process that is not completely understood. Here, we have derived free energy landscapes describing activation of the β 2 adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics (MD) simulations. The...
Article
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Solvent reorganization is a major driving force of protein–ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A2A adenosine receptor, which either interacted with...
Article
Full-text available
G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this...
Article
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Preprint
Full-text available
G protein-coupled receptors (GPCRs) shift between inactive non-signalling states and active signalling states, to which intracellular binding partners can bind. Extracellular binding of ligands stabilizes different receptor states and modulates the intracellular response via a complex and not well understood allosteric process. Despite the recent a...
Article
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A long evolution of knowledge of the psychostimulant caffeine, led in the 1960s to another purine natural product, adenosine and its A2A adenosine receptor (A2AAR). Adenosine is a short‐lived autocrine/paracrine mediator that acts pharmacologically at four ARs in a manner opposite to pan‐antagonist caffeine and serves as an endogenous allostatic re...
Article
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G protein-coupled receptors (GPCRs) are intensively studied due to their therapeutic potential as drug targets. Members of this large family of transmembrane receptor proteins mediate signal transduction in diverse cell types and play key roles in human physiology and health. In 2013 the research consortium GLISTEN (COST Action CM1207) was founded...
Article
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Rational drug design for G protein-coupled receptors (GPCRs) is limited by the small number of available atomic resolution structures. We assessed the use of homology modeling to predict the structures of two therapeutically relevant GPCRs and strategies to improve the performance of virtual screening against modeled binding sites. Homology models...
Article
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Agonist binding to G protein-coupled receptors (GPCRs) leads to conformational changes in the transmembrane region that activate cytosolic signaling pathways. Although high resolution structures of different receptor states are available, atomistic details of the allosteric signalling across the membrane remain elusive. We calculated free energy la...
Article
High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting-points for drug development. We explored if ligands of therapeutica...
Preprint
Full-text available
Agonist binding to G protein-coupled receptors (GPCRs) leads to conformational changes in the transmembrane region that activate cytosolic signaling pathways. Al-though high resolution structures of different receptor states are available, atomistic details of the allosteric signalling across the membrane remain elusive. We calculated free energy l...
Article
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Class F receptors are considered valuable therapeutic targets due to their role in human disease, but structural changes accompanying receptor activation remain unexplored. Employing population and cancer genomics data, structural analyses, molecular dynamics simulations, resonance energy transfer-based approaches and mutagenesis, we identify a con...
Article
Frizzleds (FZDs) are a group of seven transmembrane–spanning (7TM) receptors that belong to class F of the G protein–coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD 5 ) is one of the most studied...
Poster
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Understanding PAR2 active-state through a combined structure-based drug design and mutagenesis study
Article
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The A2A adenosine (A2AR) and D2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A2AR-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A2AR-D2R heteromerization and the allosteric antagonistic...
Article
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Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current...
Article
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Superoxide is a reactive oxygen species produced during aerobic metabolism in mitochondria and prokaryotes. It causes damage to lipids, proteins and DNA and is implicated in cancer, cardiovascular disease, neurodegenerative disorders and aging. As protection, cells express soluble superoxide dismutases, disproportionating superoxide to oxygen and h...
Article
Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can gui...
Article
Water plays a major role in ligand binding and is attracting increasing attention in structure-based drug design. Water molecules can make large contributions to binding affinity by bridging protein-ligand interactions or by being displaced upon complex formation, but these phenomena are challenging to model at the molecular level. Here, networks o...
Article
Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Despite that fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0....
Article
Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via p...
Article
Full-text available
Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using...
Article
Full-text available
G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we sh...
Chapter
The G protein-coupled receptor (GPCR) superfamily constitutes the largest group of human membrane proteins and plays key roles in diverse cellular processes. Major advances in structural biology for GPCRs have provided invaluable insights into ligand recognition and signaling for these important drug targets. Access to high-resolution crystal struc...
Article
Full-text available
The introduction of allosteric receptor–receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heterorecept...
Article
Peptide-recognizing G protein-coupled receptors (GPCRs) are promising therapeutic targets, but often resist drug discovery efforts. Determination of crystal structures for peptide-binding GPCRs has provided opportunities to explore structure-based methods in lead development. Molecular docking screens of two chemical libraries, containing either fr...
Article
Small molecule screening libraries cover only a small fraction of astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for...
Article
Trace Amines (TA) are side-products of the synthesis of classical neurotransmitters within the brain. TAs exert their effect by binding to a family of G protein-coupled receptors termed Trace Amine-Associated Receptors (TAARs). TAAR1 is the best characterised member of this family and studies on TAAR1 have shown that this receptor is a negative reg...
Article
Fragment-based lead discovery (FBLD) holds great promise for drug discovery, but applications to G protein-coupled receptors (GPCRs) have been limited by lack of sensitive screening techniques and scarce structural information. If virtual screening against homology models of GPCRs could be used to identify fragment ligands, FBLD could be extended t...
Article
G protein-coupled receptors (GPCRs) constitute the largest group of human membrane proteins and have received significant attention in drug discovery for their important roles in physiological processes. Drug development for GPCRs has been remarkably successful and several of the most profitable pharmaceuticals on the market target members of this...
Article
Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A2A adenosine receptor (A2AAR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by th...
Article
Achieving a molecular level understanding of G-protein coupled receptor (GPCR) activation has been a long-standing goal in biology and could be important for the development of novel drugs. Recent breakthroughs in structural biology have led to the determination of high-resolution crystal structures for the β2 adrenergic receptor (β2AR) in inactive...
Article
Despite tremendous successes of GPCR crystallog-raphy, the receptors with available structures repre-sent only a small fraction of human GPCRs. An important role of the modeling community is to maxi-mize structural insights for the remaining receptors and complexes. The community-wide GPCR Dock assessment was established to stimulate and monitor th...
Article
Full-text available
Despite tremendous successes of GPCR crystallography, the receptors with available structures represent only a small fraction of human GPCRs. An important role of the modeling community is to maximize structural insights for the remaining receptors and complexes. The community-wide GPCR Dock assessment was established to stimulate and monitor the p...
Article
The recent increase in the number of atomic-resolution structures of G protein-coupled receptors (GPCRs) has contributed to a deeper understanding of ligand binding to several important drug targets. However, reliable modeling of GPCR-ligand complexes for the vast majority of receptors with unknown structure remains to be one of the most challengin...
Article
The development of safe and effective drugs relies on the discovery of selective ligands. Serotonin (5-hydroxytryptamine [5-HT]) G protein-coupled receptors are therapeutic targets for CNS disorders but are also associated with adverse drug effects. The determination of crystal structures for the 5-HT1B and 5-HT2B receptors provided an opportunity...
Article
Fragment-based lead discovery (FBLD) is becoming an increasingly important method in drug development. We have explored the potential to complement NMR-based biophysical screening of chemical libraries with molecular docking in FBLD against the A2A adenosine receptor (A2AAR), a drug target for inflammation and Parkinson's disease. Prior to an NMR-b...
Article
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GABAA receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to GLIC, a bacterial homolog of GABAA receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking...
Article
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Proton transfer across biological membranes underpins central processes in biological systems, such as energy conservation and transport of ions and molecules. In the membrane proteins involved in these processes, proton transfer takes place through specific pathways connecting the two sides of the membrane via control elements within the protein....
Article
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Liver receptor homolog 1 (nuclear receptor LRH-1, NR5A2) is an essential regulator of gene transcription, critical for maintenance of cell pluripotency in early development and imperative for the proper functions of the liver, pancreas, and intestines during the adult life. Although physiological hormones of LRH-1 have not yet been identified, crys...
Article
Cytochrome c oxidase (CytcO) is a membrane-bound enzyme that links electron transfer from cytochrome c to O2, to proton pumping across the membrane. Protons are transferred through specific pathways that connect the protein surface with the catalytic site as well as the proton input with the proton output sides. Results from earlier studies have sh...
Article
The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A(2A) adenosine receptor (hA(2A)AR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA(2A)AR were tested in hA(1), A(2A), and A(3) radioligand binding assays and in functional assa...