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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor

G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G i/o -coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

PET Imaging Agents (FES, FFNP, and FDHT) for Estrogen, Androgen, and Progesterone Receptors to Improve Management of Breast and Prostate Cancers by Functional Imaging

Many breast and prostate cancers are driven by the action of steroid hormones on their cognate receptors in primary tumors and in metastases, and endocrine therapies that inhibit hormone production or block the action of these receptors provide clinical benefit to many but not all of these cancer patients. Because it is difficult to predict which individuals will be helped by endocrine therapies and which will not, positron emission tomography (PET) imaging of estrogen receptor (ER) and progesterone receptor (PgR) in breast cancer, and androgen receptor (AR) in prostate cancer can provide useful, often functional, information on the likelihood of endocrine therapy response in individual patients. This review covers our development of three PET imaging agents, 16α-[ 18 F]fluoroestradiol (FES) for ER, 21-[ 18 F]fluoro-furanyl-nor-progesterone (FFNP) for PgR, and 16β-[ 18 F]fluoro-5α-dihydrotestosterone (FDHT) for AR, and the evolution of their clinical use. For these agents, the pathway from concept through development tracks with an emerging understanding of critical performance criteria that is needed for successful PET imaging of these low-abundance receptor targets. Progress in the ongoing evaluation of what they can add to the clinical management of breast and prostate cancers reflects our increased understanding of these diseases and of optimal strategies for predicting the success of clinical endocrine therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Activation dynamics of a water-soluble human mu-opioid receptor

The mu-opioid receptor (MOR), a class A G protein-coupled receptor mediates opioid analgesia and remains a central target for pain therapeutics. While crystal structures of MOR exist, they provide limited insight into the receptor’s dynamic conformational landscape underlying function. Here, we engineered a thermostable water-soluble MOR variant (wsMOR) that retains native-like ligand-binding and activation dynamics. This variant enables high-yield production and detailed solution-phase structural studies that are challenging with membrane-embedded MOR, providing a valuable tool for studying receptor activation and aqueous-phase drug screening. Using a combined computational and experimental approach, we performed long-timescale all-atom molecular dynamics simulations together with neutron scattering and single-molecule FRET, revealing a structurally stable receptor with a diverse ensemble of conformations at different temporal resolutions. In the ligand-free state, wsMOR displayed high conformational flexibility, which decreased upon agonist binding, particularly in transmembrane helix 6, a hallmark of G protein-coupled receptor activation. Positive allosteric modulation and G protein binding further stabilized active-like states. These findings highlight wsMOR’s conformational plasticity across picosecond to millisecond timescales and provide a foundation for structure-guided development of next-generation opioid ligands with improved efficacy and safety.

E, Agyemang [University of Tennessee Knoxville]↗
DOE OSTI2023

Cryo-EM structures reveal native GABA A receptor assemblies and pharmacology

Type A γ-aminobutyric acid receptors (GABA A Rs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants. However, our understanding of GABA A R pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABA A R assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABA A Rs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABA A R assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation

The 48 human nuclear receptors (NRs) form a superfamily of transcription factors that regulate major physiological and pathological processes. Emerging evidence suggests that NR crosstalk can fundamentally change our understanding of NR biology, but detailed molecular mechanisms of crosstalk are lacking. Here, we report the molecular basis of crosstalk between the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), where they form a novel heterodimer, resulting in their mutual inhibition. PXR and CAR regulate drug metabolism and energy metabolism. Although they have been broadly perceived as functionally redundant, a growing number of reports suggests a mutual inhibitory relation, but their precise mode of coordinated action remains unknown. Using methods including RNA sequencing, small-angle X-ray scattering and crosslinking mass spectrometry we demonstrate that the mutual inhibition altered gene expression globally and is attributed to the novel PXR–CAR heterodimerization via the same interface used by each receptor to heterodimerize with its functional partner, retinoid X receptor (RXR). These findings establish an unexpected functional relation between PXR, CAR and RXR, change the perceived functional relation between PXR and CAR, open new perspectives on elucidating their role and designing approaches to regulate them, and highlight the importance to comprehensively investigate nuclear receptor crosstalk.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A Divergent Clade KAI2 Protein in the Root Parasitic Plant Orobanche minor Is a Highly Sensitive Strigolactone Receptor and Is Involved in the Perception of Sesquiterpene Lactones

Abstract Strigolactones (SLs) were initially discovered as germination inducers for root parasitic plants. In 2015, three groups independently reported the characterization of the SL receptor in the root parasitic plant Striga hermonthica, which causes significant damage to crop production, particularly in sub-Saharan Africa. The characterized receptors belong to HYPOSENSITIVE TO LIGHT/KARRIKIN INSENSITIVE2 (HTL/KAI2), which is a member of the α/β-hydrolase protein superfamily. In non-parasitic plants, HTL/KAI2 perceives the smoke-derived germination inducer karrikin and a yet-unidentified endogenous ligand. However, root parasitic plants evolved a specific clade of HTL/KAI2 that has diverged from the KAI2 clade of non-parasitic plants. The S. hermonthica SL receptors are included in this specific clade, which is called KAI2 divergent (KAI2d). Orobanche minor is an obligate root holoparasitic plant that grows completely dependent on the host for water and nutrients because of a lack of photosynthetic ability. Previous phylogenetic analysis of KAI2 proteins in O. minor has demonstrated the presence of at least five KAI2d clade genes. Here, we report that KAI2d3 and KAI2d4 in O. minor have the ability to act as the SL receptors. They directly interact with SLs in vitro, and when expressed in Arabidopsis, they rescue thermo-inhibited germination in response to the synthetic SL analog GR24. In particular, KAI2d3 showed high sensitivity to GR24 when expressed in Arabidopsis, suggesting that this receptor enables highly sensitive SL recognition in O. minor. Furthermore, we provide evidence that these KAI2d receptors are involved in the perception of sesquiterpene lactones, non-strigolactone-type germination inducers.

Cell Biology↗
DOE OSTI2024

Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT 1e R and 5-HT 1F R

Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT 1e R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT 1e R’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT 1e R’s pharmacology in relation to the highly homologous 5-HT 1F R, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT 1e R/5-HT 1F R agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT 1e R distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT 1e R and 5-HT 1F R contribute to the agonist activity of these antidepressants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Super-Resolution Imaging of Plant Receptor-Like Kinases Uncovers Their Colocalization and Coordination with Nanometer Resolution

Plant cell signaling often relies on the cellular organization of receptor-like kinases (RLKs) within membrane nanodomains to enhance signaling specificity and efficiency. Thus, nanometer-scale quantitative analysis of spatial organizations of RLKs could provide new understanding of mechanisms underlying plant responses to environmental stress. Here, we used stochastic optical reconstruction fluorescence microscopy (STORM) to quantify the colocalization of the flagellin-sensitive-2 (FLS2) receptor and the nanodomain marker, remorin, within Arabidopsis thaliana root hair cells. We found that recovery of FLS2 and remorin in the plasma membrane, following ligand-induced internalization by bacterial-flagellin-peptide (flg22), reached ~85% of their original membrane density after ~90 min. The pairs colocalized at the membrane at greater frequencies, compared with simulated randomly distributed pairs, except for directly after recovery, suggesting initial uncoordinated recovery followed by remorin and FLS2 pairing in the membrane. The purinergic receptor, P2K1, colocalized with remorin at similar frequencies as FLS2, while FLS2 and P2K1 colocalization occurred at significantly lower frequencies, suggesting that these RLKs mostly occupy distinct nanodomains. The chitin elicitor receptor, CERK1, colocalized with FLS2 and remorin at much lower frequencies, suggesting little coordination between CERK1 and FLS2. These findings emphasize STORM’s capacity to observe distinct nanodomains and degrees of coordination between plant cell receptors, and their respective immune pathways.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Pathways and Mechanism of Caffeine Binding to Human Adenosine A 2A Receptor

Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A 2A receptor (A 2A AR). Multiple 500–1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A 2A AR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the A 2A AR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the A 2A AR.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Mechanism of Peptide Agonist Binding in CXCR4 Chemokine Receptor

Chemokine receptors are key G-protein-coupled receptors (GPCRs) that control cell migration in immune system responses, development of cardiovascular and central nervous systems, and numerous diseases. In particular, the CXCR4 chemokine receptor promotes metastasis, tumor growth and angiogenesis in cancers. CXCR4 is also used as one of the two co-receptors for T-tropic HIV-1 entry into host cells. Therefore, CXCR4 serves as an important therapeutic target for treating cancers and HIV infection. Apart from the CXCL12 endogenous peptide agonist, previous studies suggested that the first 17 amino acids of CXCL12 are sufficient to activate CXCR4. Two 17-residue peptides with positions 1–4 mutated to RSVM and ASLW functioned as super and partial agonists of CXCR4, respectively. However, the mechanism of peptide agonist binding in CXCR4 remains unclear. Here, we have investigated this mechanism through all-atom simulations using a novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) method. The Pep-GaMD simulations have allowed us to explore representative binding conformations of each peptide and identify critical low-energy states of CXCR4 activated by the super versus partial peptide agonists. Our simulations have provided important mechanistic insights into peptide agonist binding in CXCR4, which are expected to facilitate rational design of new peptide modulators of CXCR4 and other chemokine receptors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph–Eph interfaces. One Eph–Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor–receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Structural signatures in EPR3 define a unique class of plant carbohydrate receptors

Abstract Receptor-mediated perception of surface-exposed carbohydrates like lipo- and exo-polysaccharides (EPS) is important for non-self recognition and responses to microbial associated molecular patterns in mammals and plants. In legumes, EPS are monitored and can either block or promote symbiosis with rhizobia depending on their molecular composition. To establish a deeper understanding of receptors involved in EPS recognition, we determined the structure of the Lotus japonicus ( Lotus ) exopolysaccharide receptor 3 (EPR3) ectodomain. EPR3 forms a compact structure built of three putative carbohydrate-binding modules (M1, M2 and LysM3). M1 and M2 have unique βαββ and βαβ folds that have not previously been observed in carbohydrate binding proteins, while LysM3 has a canonical βααβ fold. We demonstrate that this configuration is a structural signature for a ubiquitous class of receptors in the plant kingdom. We show that EPR3 is promiscuous, suggesting that plants can monitor complex microbial communities though this class of receptors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Structural interplay of anesthetics and paralytics on muscle nicotinic receptors

General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Structural insights into opposing actions of neurosteroids on GABA A receptors

γ-Aminobutyric acid type A (GABA A ) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA A receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA A receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA A receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Unlocking expanded flagellin perception through rational receptor engineering

Abstract The surface-localized receptor kinase FLS2 detects the flg22 epitope from bacterial flagella. FLS2 is conserved across land plants, but bacterial pathogens exhibit polymorphic flg22 epitopes. Most FLS2 homologues possess narrow perception ranges, but four with expanded perception have been identified. Using diversity analyses, AlphaFold modelling and amino acid properties, key residues enabling expanded recognition were mapped to FLS2’s concave surface, interacting with the co-receptor and polymorphic flg22 residues. Synthetic biology enabled engineering of expanded recognition from QvFLS2 (Quercus variabilis) into a homologue with canonical perception. A similar approach enabled transfer ofAgrobacteriumperception from FLS2 XL (Vitis riparia) into VrFLS2. Evolutionary analyses across three plant orders showed residues under positive selection aligning with those binding the co-receptor and flg22’s C terminus, suggesting more alleles with expanded perception exist. Our experimental data enabled the identification of specific receptor amino acid properties and AlphaFold3 metrics that facilitate predicting FLS2–flg22 recognition. This study provides a framework for rational receptor engineering to enhance pathogen restriction.

Plant Sciences↗
DOE OSTI2024

Structural bases for stoichiometry‐selective calcium potentiation of a neuronal nicotinic receptor

Background and Purpose α4β2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites of calcium binding that underpin potentiation are not known. Experimental Approach To identify calcium binding sites, we applied cryo‐electron microscopy (cryo‐EM) and molecular dynamics (MD) simulations to each stoichiometric form of the α4β2 nACh receptor in the presence of calcium ions. To test whether the identified calcium sites are linked to potentiation, we generated mutants of anionic residues at the sites, expressed wild type and mutant receptors in clonal mammalian fibroblasts, and recorded ACh‐elicited single‐channel currents with or without calcium. Key Results Both cryo‐EM and MD simulations show calcium bound to a site between the extracellular and transmembrane domains of each α4 subunit (ECD‐TMD site). Substituting alanine for anionic residues at the ECD‐TMD site abolishes stoichiometry‐selective calcium potentiation, as monitored by single‐channel patch clamp electrophysiology. Additionally, MD simulation reveals calcium association at subunit interfaces within the extracellular domain. Substituting alanine for anionic residues at the ECD sites reduces or abolishes stoichiometry‐selective calcium potentiation. Conclusions and Implications Stoichiometry‐selective calcium potentiation of the α4β2 nACh receptor is achieved by calcium association with topographically distinct sites framed by anionic residues within the α4 subunit and between the α4 and β2 subunits. Stoichiometry‐selective calcium potentiation could result from the greater number of calcium sites in the stoichiometric form with three rather than two α4 subunits. The results are relevant to modulation of signalling via α4β2 nACh receptors in physiological and pathophysiological conditions.

Pharmacology & Pharmacy↗
DOE OSTI2021

Molecular mechanisms of metabotropic GABA B receptor function

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABA B ) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABA B . Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABA B receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Structural Mechanism of an Efficacy Photoswitch Targeting the β 2 ‐adrenergic Receptor

The field of photopharmacology develops light-responsive drugs that can modulate protein activity, enabling precise and dynamic investigations of their roles in health and disease. Adrenergic receptors are prominent targets for this approach because they are prototypical G protein-coupled receptors with high clinical relevance in bronchial and cardiovascular diseases. Here, we employed the azobenzene-based compound photoazolol-1 in combination with time-resolved serial crystallography at X-ray free-electron lasers to resolve the molecular mechanisms by which photoswitchable β-blockers modulate activity of the β 2 -adrenoceptor (β 2 AR). Time-resolved structures of the receptor bound to trans-photoazolol-1 (pre-photoconversion), a strained intermediate in the nanosecond range, and the fully photoisomerized cis-photoazolol-1 reveal how isomerization of the azobenzene moiety induces distinct conformational changes within the orthosteric ligand binding pocket. Within seconds, light-excited photoazolol-1 adopts a new binding pose, altering interactions with extracellular loop 2 and shifting the positions of transmembrane helices 5, 6, and 7. Functional assays of β 2 AR in cellular membranes show that photoazolol-1 acts as an efficacy photoswitch, changing from an inverse agonist to a neutral antagonist upon isomerization without leaving the binding pocket. In combination, these findings suggest a molecular mechanism for activity modulation via efficacy photoswitches and provide a framework for designing ligands that exploit light-driven transitions within the binding pocket to achieve spatiotemporal control of receptor function.

G protein-coupled receptors↗