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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 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Ferroelectric Ordering in Nanosized PbTiO 3

The insight into the three-dimensional configuration of ferroelectric ordering in ferroelectric nanomaterials is motivated by the application of the development of functional nanodevices and the structural designing. However, the atomic deciphering of the spatial distribution of ordered structure remains challenging for the limitation of dimension and probing techniques. Here, in this paper, a neutron pair distribution function (nPDF) was utilized to analyze the spontaneous polarization distribution of zero-dimensional PbTiO 3 nanoparticles in three dimensions, via the application of reverse Monte Carlo (RMC) modeling. The comprehensive identification with transmission electron microscopy verified the linear characteristics of polarization along the c-axis in the main body, while electric polarization distribution on the surface was enhanced abnormally. In addition, the correlation of dipole vectors extending to three unit cells below the surface is retained. This work shows an application of the micro/macroscale information to effectively decode the polarization structure of nanoferroelectrics, providing new views of designing nanoferroelectric devices.

36 MATERIALS SCIENCE↗
NASA NTRS1985

Estimation of dynamic rotor loads for the rotor systems research aircraft: Methodology development and validation

The Rotor Systems Research Aircraft uses load cells to isolate the rotor/transmission systm from the fuselage. A mathematical model relating applied rotor loads and inertial loads of the rotor/transmission system to the load cell response is required to allow the load cells to be used to estimate rotor loads from flight data. Such a model is derived analytically by applying a force and moment balance to the isolated rotor/transmission system. The model is tested by comparing its estimated values of applied rotor loads with measured values obtained from a ground based shake test. Discrepancies in the comparison are used to isolate sources of unmodeled external loads. Once the structure of the mathematical model has been validated by comparison with experimental data, the parameters must be identified. Since the parameters may vary with flight condition it is desirable to identify the parameters directly from the flight data. A Maximum Likelihood identification algorithm is derived for this purpose and tested using a computer simulation of load cell data. The identification is found to converge within 10 samples. The rapid convergence facilitates tracking of time varying parameters of the load cell model in flight.

Duval, R. W.↗
DOE OSTI2019

Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure

Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. In this paper, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-aminoand 2-aryl-5-amino-substituted 3$H$-benzo[$e$][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood–brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Contact-dependent growth inhibition (CDI) systems deploy a large family of polymorphic ionophoric toxins for inter-bacterial competition

Contact-dependent growth inhibition (CDI) is a widespread form of inter-bacterial competition mediated by CdiA effector proteins. CdiA is presented on the inhibitor cell surface and delivers its toxic C-terminal region (CdiA-CT) into neighboring bacteria upon contact. Inhibitor cells also produce CdiI immunity proteins, which neutralize CdiA-CT toxins to prevent auto-inhibition. Here, we describe a diverse group of CDI ionophore toxins that dissipate the transmembrane potential in target bacteria. These CdiA-CT toxins are composed of two distinct domains based on AlphaFold2 modeling. The C-terminal ionophore domains are all predicted to form five-helix bundles capable of spanning the cell membrane. The N-terminal "entry" domains are variable in structure and appear to hijack different integral membrane proteins to promote toxin assembly into the lipid bilayer. The CDI ionophores deployed by E. coli isolates partition into six major groups based on their entry domain structures. Comparative sequence analyses led to the identification of receptor proteins for ionophore toxins from groups 1 & 3 (AcrB), group 2 (SecY) and groups 4 (YciB). Using forward genetic approaches, we identify novel receptors for the group 5 and 6 ionophores. Group 5 exploits homologous putrescine import proteins encoded by puuP and plaP, and group 6 toxins recognize di/tripeptide transporters encoded by paralogous dtpA and dtpB genes. Finally, we find that the ionophore domains exhibit significant intra-group sequence variation, particularly at positions that are predicted to interact with CdiI. Accordingly, the corresponding immunity proteins are also highly polymorphic, typically sharing only ~30% sequence identity with members of the same group. Competition experiments confirm that the immunity proteins are specific for their cognate ionophores and provide no protection against other toxins from the same group. The specificity of this protein interaction network provides a mechanism for self/nonself discrimination between E. coli isolates.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1977

Temperature dependence of Fe/++/ crystal field spectra - Implications to mineralogical mapping of planetary surfaces

Results are reported of Fe(++) crystal field spectral measurements for olivines and pyroxenes up to 400 C. The results are correlated with crystal structure data at elevated temperatures, and the validity of remote-sensed identifications of minerals on hot surfaces of the moon and Mercury is assessed. Two techniques were used to obtain spectra of minerals at elevated temperatures using a spectrophotometer. One employed a diamond cell assembly or a specially designed sample holder to measure polarized absorption spectra of heated single crystals. For the other technique, a sample holder was designed to attach to a diffuse reflectance accessory to produce reflectance spectra of heated powdered samples. Polarized absorption spectra of forsterite at 20-400 C are shown in a graph. Other graphs show the temperature dependence of Fe(++) crystal field bands in olivines, the diffuse reflectance spectra of olivine at 40-400 C, the polarization absorption spectra of orthopyroxene at 30-400 C, the diffuse reflectance spectra of pigeonite at 40-400 C, and unpolarized absorption spectra of lunar pyroxene from Apollo 15 rock 15058.

Sung, C.-M.↗
DOE OSTI2023

Genetically Encoded Crosslinking Enables Identification of Multivalent Ubiquitin‐Deubiquitylating Enzyme Interactions

Abstract Ubiquitin (Ub) proteoforms control nearly every aspect of eukaryotic cell biology through their diversity. Inspired by the widely used Ub C‐terminal electrophiles (Ub−E), here we report the identification of multivalent binding of Ub with deubiquitylating enzymes (Dubs) using genetic code expansion (GCE) and crosslinking mass spectrometry. While the Ub−Es only gather structural information with the S1 Dub sites, we demonstrate that GCE of Ub with p‐benzoyl‐L‐phenylalanine enables identification of interaction modes beyond the S1 site with a panel of Dubs of both eukaryotic and prokaryotic origin. Collectively, this represents the next generation of Ub‐based affinity probes with a unique ability to unravel Ub interaction landscapes beyond what is afforded by cysteine‐based chemistries.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Automated Bacterial Identification and Morphological Feature Analysis in Low‐Dose Cryo‐EM Using YOLOv11

Bacteria rapidly adapt to environmental cues through morphological and ultrastructural changes that correlate with physiology and behavior. Cryogenic transmission electron microscopy (cryo‐TEM) can capture these phenotypic changes in near‐native, vitrified states, but manual analysis of low‐dose micrographs is labor intensive and limits throughput. Here, we present an end‐to‐end workflow that combines low‐dose cryo‐TEM imaging with a YOLOv11‐based instance‐segmentation model to automatically identify bacteria and quantify key structural features directly from the micrographs. This workflow enables (i) robust bacterial localization and counting from low‐magnification atlas/montage images, (ii) automated measurements of cell‐envelope (outer–inner membrane) thickness and anisotropy from higher‐magnification views, and (iii) detection and quantification of bacteria–flagella interactions, including overlap length and curvature metrics for interacting versus noninteracting flagella. Using Pantoea sp. YR343 grown under distinct media conditions, we show that the automated measurements agree with manual annotations while substantially reducing analysis time. Together, these tools provide a practical framework for scalable bacterial identification and quantitative phenotyping in low‐dose cryo‐TEM datasets and establish a foundation for extending cryo‐TEM image analysis toward higher‐throughput studies of microbial heterogeneity and biointerfaces.

YOLOv11↗
DOE OSTI2018

Senescence chips for ultrahigh-throughput isolation and removal of senescent cells

Cellular senescence plays an important role in organismal aging and age-related diseases. However, it is challenging to isolate low numbers of senescent cells from small volumes of biofluids for downstream analysis. Furthermore, there is no technology that could selectively remove senescent cells in a high-throughput manner. In this work, we developed a novel microfluidic chip platform, termed senescence chip, for ultrahigh-throughput isolation and removal of senescent cells. The core component of our senescence chip is a slanted and tunable 3D micropillar array with a variety of shutters in the vertical direction for rapid cell sieving, taking advantage of the characteristic cell size increase during cellular senescence. The 3D configuration achieves high throughput, high recovery rate, and device robustness with minimum clogging. We demonstrated proof-of-principle applications in isolation and enumeration of senescent mesenchymal stem cells (MSCs) from undiluted human whole blood, and senescent cells from mouse bone marrow after total body irradiation, with the single cell resolution. After scale-up to a multilayer and multichannel structure, our senescence chip achieved ultrahigh-throughput removal of senescent cells from human whole blood with an efficiency of over 70% at a flow rate of 300 ml/hr. Sensitivity and specificity of our senescence chips could be augmented with implementation of multiscale size separation, and identification of background white blood cells using their cell surface markers such as CD45. With the advantages of high throughput, robustness, and simplicity, our senescence chips may find wide applications and contribute to diagnosis and therapeutic targeting of cellular senescence.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2001

Molecular motors and their functions in plants

Molecular motors that hydrolyze ATP and use the derived energy to generate force are involved in a variety of diverse cellular functions. Genetic, biochemical, and cellular localization data have implicated motors in a variety of functions such as vesicle and organelle transport, cytoskeleton dynamics, morphogenesis, polarized growth, cell movements, spindle formation, chromosome movement, nuclear fusion, and signal transduction. In non-plant systems three families of molecular motors (kinesins, dyneins, and myosins) have been well characterized. These motors use microtubules (in the case of kinesines and dyneins) or actin filaments (in the case of myosins) as tracks to transport cargo materials intracellularly. During the last decade tremendous progress has been made in understanding the structure and function of various motors in animals. These studies are yielding interesting insights into the functions of molecular motors and the origin of different families of motors. Furthermore, the paradigm that motors bind cargo and move along cytoskeletal tracks does not explain the functions of some of the motors. Relatively little is known about the molecular motors and their roles in plants. In recent years, by using biochemical, cell biological, molecular, and genetic approaches a few molecular motors have been isolated and characterized from plants. These studies indicate that some of the motors in plants have novel features and regulatory mechanisms. The role of molecular motors in plant cell division, cell expansion, cytoplasmic streaming, cell-to-cell communication, membrane trafficking, and morphogenesis is beginning to be understood. Analyses of the Arabidopsis genome sequence database (51% of genome) with conserved motor domains of kinesin and myosin families indicates the presence of a large number (about 40) of molecular motors and the functions of many of these motors remain to be discovered. It is likely that many more motors with novel regulatory mechanisms that perform plant-specific functions are yet to be discovered. Although the identification of motors in plants, especially in Arabidopsis, is progressing at a rapid pace because of the ongoing plant genome sequencing projects, only a few plant motors have been characterized in any detail. Elucidation of function and regulation of this multitude of motors in a given species is going to be a challenging and exciting area of research in plant cell biology. Structural features of some plant motors suggest calcium, through calmodulin, is likely to play a key role in regulating the function of both microtubule- and actin-based motors in plants.

Non-NASA Center↗
DOE OSTI2020

In Vivo Assay Reveals Microbial OleA Thiolases Initiating Hydrocarbon and β-Lactone Biosynthesis

Microbially produced β-lactones are found in antibiotic, antitumor, and antiobesity drugs. Long-chain olefinic membrane hydrocarbons have potential utility as fuels and specialty chemicals. The metabolic pathway to both end products share bacterial enzymes denoted as OleA, OleC, and OleD that transform acyl-CoA cellular intermediates into β-lactones. Bacteria producing membrane hydrocarbons via the Ole pathway additionally express a β-lactone decarboxylase, OleB. Both β-lactone and olefin biosynthesis pathways are initiated by OleA enzymes that define the overall structure of the final product. There is currently very limited information on OleA enzymes apart from the single representative from Xanthomonas campestris . In this study, bioinformatic analysis identified hundreds of new, putative OleA proteins, 74 proteins were screened via a rapid whole-cell method, leading to the identification of 25 stably expressed OleA proteins representing seven bacteria phyla.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Shotgun Immunoproteomic Approach for the Discovery of Linear B-Cell Epitopes in Biothreat Agents Francisella tularensis and Burkholderia pseudomallei

Peptide-based subunit vaccines are coming to the forefront of current vaccine approaches, with safety and cost-effective production among their top advantages. Peptide vaccine formulations consist of multiple synthetic linear epitopes that together trigger desired immune responses that can result in robust immune memory. The advantages of linear compared to conformational epitopes are their simple structure, ease of synthesis, and ability to stimulate immune responses by means that do not require complex 3D conformation. Prediction of linear epitopes through use of computational tools is fast and cost-effective, but typically of low accuracy, necessitating extensive experimentation to verify results. On the other hand, identification of linear epitopes through experimental screening has been an inefficient process that requires thorough characterization of previously identified full-length protein antigens, or laborious techniques involving genetic manipulation of organisms. In this study, we apply a newly developed generalizable screening method that enables efficient identification of B-cell epitopes in the proteomes of pathogenic bacteria. As a test case, we used this method to identify epitopes in the proteome of Francisella tularensis (Ft), a Select Agent with a well-characterized immunoproteome. Our screen identified many peptides that map to known antigens, including verified and predicted outer membrane proteins and extracellular proteins, validating the utility of this approach. We then used the method to identify seroreactive peptides in the less characterized immunoproteome of Select Agent Burkholderia pseudomallei (Bp). This screen revealed known Bp antigens as well as proteins that have not been previously identified as antigens. Although B-cell epitope prediction tools Bepipred 2.0 and iBCE-EL classified many of our seroreactive peptides as epitopes, they did not score them significantly higher than the non-reactive tryptic peptides in our study, nor did they assign higher scores to seroreactive peptides from known Ft or Bp antigens, highlighting the need for experimental data instead of relying on computational epitope predictions alone. The present workflow is easily adaptable to detecting peptide targets relevant to the immune systems of other mammalian species, including humans (depending upon the availability of convalescent sera from patients), and could aid in accelerating the discovery of B-cell epitopes and development of vaccines to counter emerging biological threats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Identification of a rare homozygous c.790C>T variation in the TFB2M gene in Korean patients with autism spectrum disorder

Highlights: • TFB2M have been known to critical in mitochondrial DNA gene expression. • We identified a variation of TFB2M gene sequence in Korean autism patients. • The variation caused increased mitochondrial DNA gene expression. • Increased mitochondrial biogenesis resulted in ROS production and damaged cells. • Structural changes of variant TFB2M seems to delay unloading of DNA from TFB2M. Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases. We identified a rare homozygous c.790C>T (His264Tyr) variation in TFB2M gene in two Korean siblings with ASD by whole-exome sequencing. The roles of the TFB2M variation in the pathogenesis of ASD were investigated. Patient fibroblasts revealed increased transcription of mitochondrial genes and mitochondrial function in terms of ATP, membrane potential, oxygen consumption, and reactive oxygen species (ROS). Overexpression of the TFB2M variant in primary-cultured fibroblasts demonstrated significantly increased transcription of mitochondrial genes and mitochondrial function compared with overexpression of wild-type TFB2M. Molecular dynamics simulation of the TFB2M variant protein suggested an increase in the rigidity of the hinge region, which may cause alterations in loading and/or unloading of TFB2M on target DNA. Our results suggest that augmentation of mitochondrial gene expression and subsequent enhancement of mitochondrial function may be associated with the pathogenesis of ASD in Korean patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

The Zintl pnictides Yb10CdSb9 and Yb14CdSb11: New candidate thermoelectric materials

The synthesis of new materials is the lifeline of solid-state science, and it continues to offer us unique opportunities for testing various theoretical formulations and models on a practical material. Such an avenue, therefore, provides a breeding ground for technological innovations and advancements that can completely revolutionize our world. Here, we report the results of our exploratory syntheses in the Yb–Cd–Sb compositional space that lead to the identification of two new Zintl antimonides, namely, Yb10CdSb9 and Yb14CdSb11. Their crystal structures were established via single-crystal X-ray diffraction methods; the basic electronic and transport properties of the new materials were also characterized. Yb10CdSb9 crystallizes in a disordered variant of the tetragonal Ca10LiMgSb9 structure type with unit cell parameters a = 11.8473(8) Å and c = 17.1302(12) Å (space group P42/mnm). Yb14CdSb11 crystallizes in the tetragonal Ca14AlSb11 structure type with unit cell parameters: a = 16.605(3) Å and c = 12.144(7) Å (space group I41/acd). Although the structures of both compounds can be rationalized within the framework of the Zintl formalism, based on the partitioning of the valence electrons in the much disordered Yb10CdSb9 phase, the charge is indicative of a slightly electron-rich composition. Electronic structure calculations in both cases support the notion of intrinsic semiconductor behavior, as expected for a Zintl phase. The temperature dependence of the electrical resistivity of a single crystal of Yb10CdSb9 is in line with that, and the evolution of the Seebeck coefficient indicates an electron-dominated transport mechanism, and a respectable power factor of 0.71 μW/cm K2 at 460 K can be calculated for Yb10CdSb9. The electrical resistivity of Yb14CdSb11, however, evolves in a semimetallic manner, which could suggest an overdoped sample or degenerate semiconducting behavior.

Ogunbunmi, Michael O. (ORCID:0000000253409198)↗
DOE OSTI2019

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED 90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1991

Bifunctional alkaline oxygen electrodes

The authors describe the identification and testing of electrocatalysts and supports for the positive electrode of moderate-temperature, single-unit, rechargeable alkaline fuel cells. Recent work on Na(x)Pt3O4, a potential bifunctional catalyst, is described, as well as the application of novel approaches to the development of more efficient bifunctional electrode structures. The three dual-character electrodes considered here showed similar superior performance; the Pt/RhO2 and Rh/RhO2 electrodes showed slightly better performance than the Pt/IrO2 electrode. It is concluded that Na(x)Pt3O4 continues to be a promising bifunctional oxygen electrode catalyst but requires further investigation and development.

Swette, L.↗
DOE OSTI2019

Novel T9 loop conformation of filamenting temperature-sensitive mutant Z from Mycobacterium tuberculosis

As of 2017, tuberculosis had infected 1.7 billion people (23% of the population of the world) and caused ten million deaths. Mycobacterium tuberculosis (Mtb) is quickly evolving, and new strains are classified as multidrug resistant. Thus, the identification of novel druggable targets is essential to combat the proliferation of these drug-resistant strains. Filamenting temperature-sensitive mutant Z (FtsZ) is a key protein involved in cytokinesis, an important process for Mtb proliferation and viability. FtsZ is required for bacterial cell division because it polymerizes into a structure called the Z-ring, which recruits accessory division proteins to the septum. Here, the crystal structure of the MtbFtsZ protein has been determined to 3.46 Å resolution and is described as a dimer of trimers, with an inter-subunit interface between protomers AB and DE . In this work, a novel conformation of MtbFtsZ is revealed involving the T9 loop and the nucleotide-binding pocket of protomers BC and EF .

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

DOE new players Carbon cycle (2016-2021)

The overarching scientific goals of our multidisciplinary grant was to further expand understanding about the key microorganisms (players), metabolic strategies (processes), and interspecies relationships (interactions) involved in the formation and oxidation of methane in the environment. This research applied novel environmental metagenomics, transcriptomics, and proteomic techniques, state-of-the-art analytical imaging, stable isotope geochemistry, and reaction-transport modeling to address these goals and develop an ‘ecosystems level’ understanding of the factors which regulate microbial methane cycling in anoxic sedimentary ecosystems. For decades, it was believed that the obligate step in methanogenesis catalyzed by methyl coenzyme M reductase (Mcr) was limited to a specific branch of the archaeal Domain, formerly known as the Euryarchaeota. Less than a decade ago co-I Tyson’s team published a surprising metagenomic-based discovery of divergent Mcr genes in a novel uncultured phylum (Bathyarchaeota), catalyzing a major shift in thinking about the diversity of microorganisms that encode the potential for methane (or higher alkane) metabolism in anoxic environments (Evans et al., 2015). In our work here, we further expand on the groups of archaea harboring the genomic potential for methane or hydrocarbon metabolism using environmental metagenomics and new gene targeted bioinformatics techniques. We additionally advanced understanding about the terminal electron acceptors and metabolic potential supporting the anaerobic oxidation of methane (AOM) in terrestrial ecosystems, specifically focused on new lineages of ANME archaea capable of respiring manganese oxides with methane presumably using large extracellular multi-heme cytochrome complexes. New details about specific syntrophic mechanisms underlying the exchange of electrons during sulfate-coupled methane oxidation between ANME-2 archaea and their sulfate-reducing bacterial partners were also elucidated as part of this funded project. Through a series of experimental ‘omics and single cell stable isotope probing studies with incubated environmental sediment samples and a cultured model electrogenic microorganism combined with model-based predictions. Combined, this work provides strong support for the hypothesis of direct interspecies electron transfer (DIET) is the dominant syntrophic mechanism controlling the anaerobic oxidation of methane with sulfate over other proposed mechanisms and additionally illustrates important spatial constraints and the underlying physico-chemical factors influencing AOM syntrophic consortia structure for DIET and extracellular metal respiration. This collaborative multi-institutional project successfully advanced several of our milestone goals including the identification of new microbial players containing methyl coenzyme M reductases hypothesized to be central to methane or hydrocarbon cycling in anoxic environments and enhancing fundamental knowledge about the role extracellular electron transfer plays in the ecophysiology of methanotrophic archaea respiring metal oxides and in the physical and metabolic structuring of syntrophic interactions in methane-rich sedimentary ecosystems.

03 NATURAL GAS↗
DOE OSTI2019

Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening

Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3' end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

Lountos, George T.↗