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At least 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design

Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3

Abstract Replication of the coronavirus genome starts with the formation of viral RNA-containing double-membrane vesicles (DMV) following viral entry into the host cell. The multi-domain nonstructural protein 3 (nsp3) is the largest protein encoded by the known coronavirus genome and serves as a central component of the viral replication and transcription machinery. Previous studies demonstrated that the highly-conserved C-terminal region of nsp3 is essential for subcellular membrane rearrangement, yet the underlying mechanisms remain elusive. Here we report the crystal structure of the CoV-Y domain, the most C-terminal domain of the SARS-CoV-2 nsp3, at 2.4 Å-resolution. CoV-Y adopts a previously uncharacterized V-shaped fold featuring three distinct subdomains. Sequence alignment and structure prediction suggest that this fold is likely shared by the CoV-Y domains from closely related nsp3 homologs. NMR-based fragment screening combined with molecular docking identifies surface cavities in CoV-Y for interaction with potential ligands and other nsps. These studies provide the first structural view on a complete nsp3 CoV-Y domain, and the molecular framework for understanding the architecture, assembly and function of the nsp3 C-terminal domains in coronavirus replication. Our work illuminates nsp3 as a potential target for therapeutic interventions to aid in the on-going battle against the COVID-19 pandemic and diseases caused by other coronaviruses.

36 MATERIALS SCIENCE↗
DOE OSTI2022

The first crystal structures of hybrid and parallel four-tetrad intramolecular G-quadruplexes

Abstract G-quadruplexes (GQs) are non-canonical DNA structures composed of stacks of stabilized G-tetrads. GQs play an important role in a variety of biological processes and may form at telomeres and oncogene promoters among other genomic locations. Here, we investigate nine variants of telomeric DNA from Tetrahymena thermophila with the repeat (TTGGGG)n. Biophysical data indicate that the sequences fold into stable four-tetrad GQs which adopt multiple conformations according to native PAGE. Excitingly, we solved the crystal structure of two variants, TET25 and TET26. The two variants differ by the presence of a 3′-T yet adopt different GQ conformations. TET25 forms a hybrid [3 + 1] GQ and exhibits a rare 5′-top snapback feature. Consequently, TET25 contains four loops: three lateral (TT, TT, and GTT) and one propeller (TT). TET26 folds into a parallel GQ with three TT propeller loops. To the best of our knowledge, TET25 and TET26 are the first reported hybrid and parallel four-tetrad unimolecular GQ structures. The results presented here expand the repertoire of available GQ structures and provide insight into the intricacy and plasticity of the 3D architecture adopted by telomeric repeats from T. thermophila and GQs in general.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi

Rho family GTPases regulate an array of cellular processes and are often modulated by pathogens to promote infection. In this work, we identify a cryptic guanine nucleotide exchange factor (GEF) domain in the OtDUB protein encoded by the pathogenic bacterium Orientia tsutsugamushi. A proteomics-based OtDUB interaction screen identified numerous potential host interactors, including the Rho GTPases Rac1 and Cdc42. We discovered a domain in OtDUB with Rac1/Cdc42 GEF activity (OtDUB GEF ), with higher activity toward Rac1 in vitro. While this GEF bears no obvious sequence similarity to known GEFs, crystal structures of OtDUB GEF alone (3.0 Å) and complexed with Rac1 (1.7 Å) reveal striking convergent evolution, with a unique topology, on a V-shaped bacterial GEF fold shared with other bacterial GEF domains. Structure-guided mutational analyses identified residues critical for activity and a mechanism for nucleotide displacement. Ectopic expression of OtDUB activates Rac1 preferentially in cells, and expression of the OtDUBGEF alone alters cell morphology. Cumulatively, this work reveals a bacterial GEF within the multifunctional OtDUB that co-opts host Rac1 signaling to induce changes in cytoskeletal structure.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

High-resolution crystal structure of the Borreliella burgdorferi PlzA protein in complex with c-di-GMP: new insights into the interaction of c-di-GMP with the novel xPilZ domain

ABSTRACT In the tick-borne pathogens, Borreliella burgdorferi and Borrelia hermsii, c-di-GMP is produced by a single diguanylate cyclase (Rrp1). In these pathogens, the Plz proteins (PlzA, B and C) are the only c-di-GMP receptors identified to date and PlzA is the sole c-di-GMP receptor found in all Borreliella isolates. Bioinformatic analyses suggest that PlzA has a unique PilZN3-PilZ architecture with the relatively uncommon xPilZ domain. Here, we present the crystal structure of PlzA in complex with c-di-GMP (1.6 Å resolution). This is the first structure of a xPilz domain in complex with c-di-GMP to be determined. PlzA has a two-domain structure, where each domain comprises topologically equivalent PilZ domains with minimal sequence identity but remarkable structural similarity. The c-di-GMP binding site is formed by the linker connecting the two domains. While the structure of apo PlzA could not be determined, previous fluorescence resonance energy transfer data suggest that apo and holo forms of the protein are structurally distinct. The information obtained from this study will facilitate ongoing efforts to identify the molecular mechanisms of PlzA-mediated regulation in ticks and mammals.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Crystal structure of a cap-independent translation enhancer RNA

In eukaryotic messenger RNAs, the 5' cap structure binds to the translation initiation factor 4E to facilitate early stages of translation. Although many plant viruses lack the 5' cap structure, some contain cap-independent translation elements (CITEs) in their 3' untranslated region. The PTE (Panicum mosaic virus translation element) class of CITEs contains a G-rich asymmetric bulge and a C-rich helical junction that were proposed to interact via formation of a pseudoknot. SHAPE analysis of PTE homologs reveals a highly reactive guanosine residue within the G-rich region proposed to mediate eukaryotic initiation factor 4E (eIF4E) recognition. Here we have obtained the crystal structure of the PTE from Pea enation mosaic virus 2 (PEMV 2 ) RNA in complex with our structural chaperone, Fab BL3–6. The structure reveals that the G-rich and C-rich regions interact through a complex network of interactions distinct from those expected for a pseudoknot. The motif, which contains a short parallel duplex, provides a structural mechanism for how the guanosine is extruded from the core stack to enable eIF4E recognition. Homologous PTE elements harbor a G-rich bulge and a three-way junction and exhibit covariation at crucial positions, suggesting that the PEMV 2 tertiary architecture is conserved among these homologs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Crystal structure of ultra-humanized anti-pTau Fab reveals how germline substitutions humanize CDRs without loss of binding’

Administration of therapeutic antibodies can elicit adverse immune responses in patients through the generation of anti-drug antibodies that, in turn, reduce the efficacy of the therapeutic. Removal of foreign amino acid content by humanization can lower the immunogenic risk of the therapeutic mAb. We previously developed the ultra-humanization technology “Augmented Binary Substitution” (ABS) which enables single-step CDR germlining of antibodies. The application of ABS to a chicken anti-pTau antibody generated an ultra-humanized variant, anti-pTau C21-ABS, with increased human amino acid content in the CDRs and reduced in-silico predicted immunogenicity risk. Here, we report the high-resolution crystal structure of anti-pTau C21-ABS Fab in complex with the pTau peptide (7KQK). This study examines how ultra-humanization, via CDR germlining, is facilitated while maintaining near-identical antigen affinity (within 1.6-fold). The co-complex structure reveals that the ABS molecule targets the same antigenic epitope, accommodated by structurally-similar changes in the paratope. These findings confirm that ABS enables the germlining of amino acids within CDRs by exploiting CDR plasticity, to reduce non-human amino acid CDR content, with few alterations to the overall mechanism of binding.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition

Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound’s interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Crystal structure of vancomycin bound to the resistance determinant D -alanine- D -serine

Vancomycin is a glycopeptide antibiotic that for decades has been a mainstay of treatment for persistent bacterial infections. However, the spread of antibiotic resistance threatens its continued utility. In particular, vancomycin-resistant enterococci (VRE) have become a pressing clinical challenge. Vancomycin acts by binding and sequestering the intermediate Lipid II in cell-wall biosynthesis, specifically recognizing a D-alanine-D-alanine dipeptide motif within the Lipid II molecule. VRE achieve resistance by remodeling this motif to either D-alanine-D-lactate or D-alanine-D-serine; the former substitution essentially abolishes recognition by vancomycin of Lipid II, whereas the latter reduces the affinity of the antibiotic by roughly one order of magnitude. The complex of vancomycin bound to D-alanine-D-serine has been crystallized, and its 1.20 Å X-ray crystal structure is presented here. This structure reveals that the D-alanine-D-serine ligand is bound in essentially the same position and same pose as the native D-alanine-D-alanine ligand. The serine-containing ligand appears to be slightly too large to be comfortably accommodated in this way, suggesting one possible contribution to the reduced binding affinity. In addition, two flexible hydroxyl groups – one from the serine side chain of the ligand, and the other from a glucose sugar on the antibiotic – are locked into single conformations in the complex, which is likely to contribute an unfavorable entropic component to the recognition of the serine-containing ligand.

36 MATERIALS SCIENCE↗
DOE OSTI2022

The interaction between transport-segment DNA and topoisomerase IA—crystal structure of MtbTOP1 in complex with both G- and T-segments

Abstract Each catalytic cycle of type IA topoisomerases has been proposed to comprise multistep reactions. The capture of the transport-segment DNA (T-segment) into the central cavity of the N-terminal toroidal structure is an important action, which is preceded by transient gate-segment (G-segment) cleavage and succeeded by G-segment religation for the relaxation of negatively supercoiled DNA and decatenation of DNA. The T-segment passage in and out of the central cavity requires significant domain–domain rearrangements, including the movement of D3 relative to D1 and D4 for the opening and closing of the gate towards the central cavity. Here we report a direct observation of the interaction of a duplex DNA in the central cavity of a type IA topoisomerase and its associated domain–domain conformational changes in a crystal structure of a Mycobacterium tuberculosis topoisomerase I complex that also has a bound G-segment. The duplex DNA within the central cavity illustrates the non-sequence-specific interplay between the T-segment DNA and the enzyme. The rich structural information revealed from the novel topoisomerase–DNA complex, in combination with targeted mutagenesis studies, provides new insights into the mechanism of the topoisomerase IA catalytic cycle.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Crystal structure of MbnF: an NADPH-dependent flavin monooxygenase from Methylocystis strain SB2

Methanobactins (MBs) are ribosomally produced and post-translationally modified peptides (RiPPs) that are used by methanotrophs for copper acquisition. The signature post-translational modification of MBs is the formation of two heterocyclic groups, either an oxazolone, pyrazinedione or imidazolone group, with an associated thioamide from an X -Cys dipeptide. The precursor peptide (MbnA) for MB formation is found in a gene cluster of MB-associated genes. The exact biosynthetic pathway of MB formation is not yet fully understood, and there are still uncharacterized proteins in some MB gene clusters, particularly those that produce pyrazinedione or imidazolone rings. One such protein is MbnF, which is proposed to be a flavin monooxygenase (FMO) based on homology. To help to elucidate its possible function, MbnF from Methylocystis sp. strain SB2 was recombinantly produced in Escherichia coli and its X-ray crystal structure was resolved to 2.6 Å resolution. Based on its structural features, MbnF appears to be a type A FMO, most of which catalyze hydroxylation reactions. Preliminary functional characterization shows that MbnF preferentially oxidizes NADPH over NADH, supporting NAD(P)H-mediated flavin reduction, which is the initial step in the reaction cycle of several type A FMO enzymes. It is also shown that MbnF binds the precursor peptide for MB, with subsequent loss of the leader peptide sequence as well as the last three C-terminal amino acids, suggesting that MbnF might be needed for this process to occur. Finally, molecular-dynamics simulations revealed a channel in MbnF that is capable of accommodating the core MbnA fragment minus the three C-terminal amino acids.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Crystal structure and magnetism of actinide oxides: a review

In actinide systems, the 5f electrons experience a uniquely delicate balance of effects and interactions having similar energy scales, which are often difficult to properly disentangle. This interplay of factors such as the dual nature of 5f-states, strong electronic correlations, and strong spin–orbit coupling results in electronically unusual and intriguing behavior such as multi-k antiferromagnetic ordering, multipolar ordering, Mott-physics, mixed valence configurations, and more. Despite the inherent allure of their exotic properties, the exploratory science of even the more basic, binary systems like the actinide oxides has been limited due to their toxicity, radioactivity, and reactivity. In this article, we provide an overview of the available synthesis techniques for selected binary actinide oxides, including the actinide dioxides, sesquioxides, and a selection of higher oxides. For these oxides, here we also review and evaluate the current state of knowledge of their crystal structures and magnetic properties. In many aspects, substantial knowledge gaps exist in the current body of research on actinide oxides related to understanding their electronic ground states. Bridging these gaps is vital for improving not only a fundamental understanding of these systems but also of future nuclear technologies. To this end, we note the experimental techniques and necessary future investigations which may aid in better elucidating the nature of these fascinating systems.

36 MATERIALS SCIENCE↗
DOE OSTI2024

Crystal structure solution and high-temperature thermal expansion in NaZr 2 (PO 4 ) 3 -type materials

The NaZr 2 P 3 O 12 family of materials have shown low and tailorable thermal expansion properties. In this study, SrZr 4 P 6 O 24 (SrO·4ZrO 2 ·3P 2 O 5 ), CaZr 4 P 6 O 24 (CaO·4ZrO 2 ·3P 2 O 5 ), MgZr 4 P 6 O 24 (MgO·4ZrO 2 ·3P 2 O 5 ), NaTi 2 P 3 O 12 [½(Na 2 O·4TiO 2 ·3P 2 O 5 )], NaZr 2 P 3 O 12 [½(Na 2 O·4ZrO 2 ·3P 2 O 5 )], and related solid solutions were synthesized using the organic–inorganic steric entrapment method. The samples were characterized by in-situ high-temperature X-ray diffraction from 25 to 1500°C at the Advanced Photon Source and National Synchrotron Light Source II. The average linear thermal expansion of SrZr 4 P 6 O 24 and CaZr 4 P 6 O 24 was between −1 × 10 −6 per °C and 6 × 10 −6 per °C from 25 to 1500°C. The crystal structures of the high-temperature polymorphs of CaZr 4 P 6 O 24 and SrZr 4 P 6 O 24 with R 3 c symmetry were solved by Fourier difference mapping and Rietveld refinement. This polymorph is present above ∼1250°C. This work measured thermal expansion coefficients to 1500°C for all samples and investigated the differences in thermal expansion mechanisms between polymorphs and between compositions.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Nickel(ii) complexes based on dithiolate–polyamine binary ligand systems: crystal structures, hirshfeld surface analysis, theoretical study, and catalytic activity study on photocatalytic hydrogen generation

To ascertain the influence of binary ligand systems [1,1-dicyanoethylene-2,2-dithiolate (i-mnt -2 ) and polyamine {tetraen = tris(2-aminoethyl)amine, tren = diethylene triamine and opda = o-phenylenediamine}] on the coordination modes of the Ni(II) metal center and resulting supramolecular architectures, a series of nickel(II) thiolate complexes [Ni(tetraen)(i-mnt)](DMSO) (1), [Ni 2 (tren) 2 (i-mnt) 2 ] (2), and [Ni 2 (i-mnt) 2 (opda) 2 ] n (3) have been synthesized in high yield in one step in water and structurally characterized by single crystal X-ray crystallography and spectroscopic techniques. X-ray diffraction studies disclose the diverse i-mnt -2 coordination to the Ni +2 center in the presence of active polyamine ligands, forming a slightly distorted octahedral geometry (NiN 4 S 2 ) in 1, square planar (NiS 4 ) and distorted octahedral geometries (NiN 6 ) in the bimetallic co-crystallized aggregate of cationic [Ni(tren) 2 ] +2 and anionic [Ni(i-mnt) 2 ] -2 in 2, and a one dimensional (1D) polymeric chain along the [100] axis in 3, having consecutive square planar (NiS 4 ) and octahedral (NiN 6 ) coordination kernels. The N–H···O, N–H···S, N–H···N, N–H···S, N–H···N, and N–H···O type hydrogen bonds stabilize the supramolecular assemblies in 1, 2, and 3 respectively imparting interesting graph-set-motifs. The molecular Hirshfeld surface analyses (HS) and 2D fingerprint plots were utilized for decoding all types of non-covalent contacts in the crystal networks. Atomic HS analysis of the Ni +2 centers reveals significant Ni–N metal–ligand interactions compared to Ni–S interactions. We have also studied the unorthodox interactions observed in the solid state structures of 1–3 by QTAIM and NBO analyses. Moreover, all the complexes proved to be highly active water reduction co-catalysts (WRC) in a photo-catalytic hydrogen evolution process involving iridium photosensitizers, wherein 2 and 3 having a square planar arrangement around the nickel center(s) – were found to be the most active ones, achieving 1000 and 1119 turnover numbers (TON), respectively.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Interplay of Crystal Structure and Magnetic Properties of the Eu 5.08-x Sr x Al 3 Sb 6 Solid Solution

Zintl phases containing rare-earth metals have gained attention due to their magnetic, electronic, and thermoelectric properties. Eu 5.08 Al 3 Sb 6 is a new structure type (monoclinic space group C2/m) that can be described as a pseudorock-salt EuSb motif with the Eu-centered Sb octahedra at the origin of the unit cell, and on the C-face center, containing either Eu (8%) or an Al 4 tetrahedron modeled as a dual tetrahedron (37.5%). The complete solid solution of Eu 5.08–x Sr x Al 3 Sb 6 can be prepared; however, the cation totals vacillate from 5 to 5.24 depending on the Al content. Al K-edge XANES shows a shift to higher energy relative to the Al metal but at slightly lower energy relative to AlSb, indicating an intermediate oxidation state closer to +3 than 0. The lack of an Al K-edge shift with the incorporation of Sr suggests that changes in Sr content do not have a meaningful impact on the electronics of the Al tetrahedra. Investigation of the solid solution structures provides evidence for classifying this structure type as a polar intermetallic phase with variable composition. Magnetization measurements were collected for the solid solution and show complex magnetic ordering with competing ferromagnetic and antiferromagnetic interactions as the Sr content increases.

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

Crystal Structures, Optical Behavior, and Magnetic Properties in Hydrated Lanthanide Iron Sulfates

Single crystals of LnFe(SO 4 ) 3 (H 2 O) 2 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Dy, Ho, Er, Tm; compounds 1–11) and LnFe(SO 4 ) 3 (H 2 O) (Ln = Tm, Yb, Lu; compounds 12–14) were synthesized under hydrothermal conditions. Single-crystal X-ray diffraction (SCXRD) analysis revealed that the dihydrated compounds (1–11) crystallize in centrosymmetric (CS) structures, with the lanthanide ions adopting eight-coordinate geometries. In contrast, the monohydrated compounds (12–14) exhibit noncentrosymmetric (NCS) structures, where the lanthanide ions are seven-coordinated. Vibrating sample magnetometry (VSM) confirmed that compounds 2, 4, and 7–11 are paramagnetic below 400 K, with compound 8 displaying the highest magnetic susceptibility. Compounds 1, 5, 6, 13, and 14 show a sharp increase in magnetic susceptibility at Néel temperatures ( T N ) of approximately 72, 76, 70, 58, and 56 K, respectively, indicating antiferromagnetic ordering. High-temperature magnetic susceptibility measurements further support the presence of antiferromagnetic transitions in these compounds. Second harmonic generation (SHG) measurements showed that the noncentrosymmetric Yb (compound 13) and Lu (compound 14) compounds exhibit SHG intensities of 0.3× and 1.6× that of potassium dihydrogen phosphate (KDP), respectively.

anions↗
DOE OSTI2020

Using Complementary Methods of Synchrotron Radiation Powder Diffraction and Pair Distribution Function to Refine Crystal Structures with High Quality Parameters—A Review

Determination of the atomic-scale structures of certain fine-grained minerals using single-crystal X-ray diffraction (XRD) has been challenging because they commonly occur as submicron and nanocrystals in the geological environment. Synchrotron powder diffraction and scattering techniques are useful complementary methods for studying this type of minerals. In this review, we discussed three example studies investigated by combined methods of synchrotron radiation XRD and pair distribution function (PDF) techniques: (1) low-temperature cristobalite; (2) kaolinite; and (3) vernadite. Powder XRD is useful to determine the average structure including unit-cell parameters, fractional atomic coordinates, occupancies and isotropic atomic displacement parameters. X-ray/Neutron PDF methods are sensitive to study the local structure with anisotropic atomic displacement parameters (ADP). The results and case studies suggest that the crystal structure and high-quality ADP values can be obtained using the combined methods. The method can be useful to characterize crystals and minerals that are not suitable for single-crystal XRD.

58 GEOSCIENCES↗