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At least 73 records · Page 4

Structural basis of sequence-specific cytosine deamination by double-stranded DNA deaminase toxin DddA

The interbacterial deaminase toxin DddA catalyzes cytosine-to-uracil conversion in double-stranded (ds) DNA and enables CRISPR-free mitochondrial base editing, but the molecular mechanisms underlying its unique substrate selectivity have remained elusive. Here, we report crystal structures of DddA bound to a dsDNA substrate containing the 5'-TC target motif. These structures show that DddA binds to the minor groove of a sharply bent dsDNA and engages the target cytosine extruded from the double helix. DddA Phe1375 intercalates in dsDNA and displaces the 5' (-1) thymine, which in turn replaces the target (0) cytosine and forms a noncanonical T–G base pair with the juxtaposed guanine. This tandem displacement mechanism allows DddA to locate a target cytosine without flipping it into the active site. Biochemical experiments demonstrate that DNA base mismatches enhance the DddA deaminase activity and relax its sequence selectivity. On the basis of the structural information, we further identified DddA mutants that exhibit attenuated activity or altered substrate preference. Our studies may help design new tools useful in genome editing or other applications.

59 BASIC BIOLOGICAL SCIENCES↗

Tunable allosteric library of caspase-3 identifies coupling between conserved water molecules and conformational selection

The native ensemble of caspases is described globally by a complex energy landscape where the binding of substrate selects for the active conformation, whereas targeting an allosteric site in the dimer interface selects an inactive conformation that contains disordered active-site loops. Mutations and posttranslational modifications stabilize high-energy inactive conformations, with mostly formed, but distorted, active sites. To examine the interconversion of active and inactive states in the ensemble, we used detection of related solvent positions to analyze 4,995 waters in 15 high-resolution (<2.0 Å) structures of wild-type caspase-3, resulting in 450 clusters with the most highly conserved set containing 145 water molecules. The data show that regions of the protein that contact the conserved waters also correspond to sites of posttranslational modifications, suggesting that the conserved waters are an integral part of allosteric mechanisms. To test this hypothesis, we created a library of 19 caspase-3 variants through saturation mutagenesis in a single position of the allosteric site of the dimer interface, and we show that the enzyme activity varies by more than four orders of magnitude. Altogether, our database consists of 37 high-resolution structures of caspase-3 variants, and we demonstrate that the decrease in activity correlates with a loss of conserved water molecules. Furthermore, the data show that the activity of caspase-3 can be fine-tuned through globally desolvating the active conformation within the native ensemble, providing a mechanism for cells to repartition the ensemble and thus fine-tune activity through conformational selection.

59 BASIC BIOLOGICAL SCIENCES↗

Structural and biochemical characterization of AidC, a quorum-quenching lactonase with atypical selectivity

Quorum-quenching catalysts are of interest for potential application as biochemical tools for interrogating interbacterial communication pathways, as antibiofouling agents, and as anti-infective agents in plants and animals. Herein, the structure and function of AidC, an N-acyl-l-homoserine lactone (AHL) lactonase from Chryseobacterium , is characterized. Steady-state kinetics show that zinc-supplemented AidC is the most efficient wild-type quorum-quenching enzymes characterized to date, with a k cat /K M value of approximately 2 × 10 6 M -1 s -1 for N-heptanoyl-l-homoserine lactone. The enzyme has stricter substrate selectivity and significantly lower KM values (ca. 50 μM for preferred substrates) compared to those of typical AHL lactonases (ca. >1 mM). X-ray crystal structures of AidC alone and with the product N-hexanoyl-l-homoserine were determined at resolutions of 1.09 and 1.67 Å, respectively. Each structure displays as a dimer, and dimeric oligiomerization was also observed in solution by size-exclusion chromatography coupled with multiangle light scattering. Lastly, the structures reveal two atypical features as compared to previously characterized AHL lactonases: a "kinked" α-helix that forms part of a closed binding pocket that provides affinity and enforces selectivity for AHL substrates and an active-site His substitution that is usually found in a homologous family of phosphodiesterases. We discuss implications for the catalytic mechanism of AHL lactonases.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Data Science-Driven Analysis of Substrate-Permissive Diketopiperazine Reverse Prenyltransferase NotF: Applications in Protein Engineering and Cascade Biocatalytic Synthesis of (-)-Eurotiumin A

Prenyltransfer is an early-stage carbon-hydrogen bond (C-H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan diketopiperazine (DKP) alkaloids. Toward the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). As the first tailoring event within the biosynthesis of cytotoxic notoamide metabolites, PT NotF catalyzes C2 reverse prenyltransfer of brevianamide F. Solving a crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent-exposed active site, intimating NotF may possess a significantly broad substrate scope. To assess the substrate selectivity of NotF, we synthesized a panel of 30 sterically and electronically differentiated tryptophanyl DKPs, the majority of which were selectively prenylated by NotF in synthetically useful conversions (2 to > 99%). Quantitative representation of this substrate library and development of a descriptive statistical model provided insight into the molecular origins of NotF's substrate promiscuity. This approach enabled the identification of key substrate descriptors (electrophilicity, size, and flexibility) that govern the rate of NotF-catalyzed prenyltransfer, and the development of an "induced fit docking (IFD)-guided" engineering strategy for improved turnover of our largest substrates. We further demonstrated the utility of NotF in tandem with oxidative cyclization using flavin monooxygenase, BvnB. This one-pot, in vitro biocatalytic cascade enabled the first chemoenzymatic synthesis of the marine fungal natural product, (-)-eurotiumin A, in three steps and 60% overall yield.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Mechanism-Based Design of Green Oxidation Catalysts

In modern era of scarce resources, developing chemical processes that can eventually generate useful materials and fuels from readily available, simple, cheap, renewable starting materials is of paramount importance. Small molecules, such as dioxygen, dinitrogen, water, or carbon dioxide, can be viewed as ideal sources of oxygen, nitrogen, or carbon atoms in synthetic applications. Living organisms perfected the art of utilizing small molecules in biosynthesis and in generating energy; photosynthesis, which couples carbohydrate synthesis from carbon dioxide with photocatalytic water splitting, is but one impressive example of possible catalytic processes. Small molecule activation in synthetic systems remains challenging, and current efforts are focused on developing catalytic reactions that can convert small molecules into useful building blocks for generating more complicated organic molecules, including fuels. Modeling nature is attractive in many respects, including the possibility to use non-toxic, earth-abundant metals in catalysis. Specific systems investigated in our work include biomimetic catalytic oxidations with dioxygen, hydrogen peroxide, and related oxygen atom donors. More recently, a new direction was been also pursued in the group, fixation of carbon dioxide with transition metal complexes. Mechanistic understanding of biomimetic metal-catalyzed oxidations is critical for the design of functional models of metalloenzymes, and ultimately for the rational synthesis of useful, selective and efficient oxidation catalysts utilizing dioxygen and hydrogen peroxide as terminal oxidants. All iron oxidases and oxygenases (both mononuclear and dinuclear) utilize metal-centered intermediates as reactive species in selective substrate oxidation. In contrast, free radical pathways (Fenton chemistry) are common for traditional inorganic iron compounds, producing hydroxyl radicals as very active, non-selective oxidants. Recent developments, however, changed this situation. Growing families of synthetic iron complexes that resemble active sites of metalloenzymes produce metal-based intermediates (rather than hydroxyl radicals) in reactions with oxygen donors. These complexes are very promising for selective oxygen and peroxide activation. In order to understand the mechanisms of metal-based small molecule activation, kinetically competent metal-oxygen intermediates must be identified. One of the grand challenges identified by the Department of Energy workshop "Catalysis for Energy" is understanding mechanisms and dynamics of catalyzed reactions. The research summarized herein focuses on detailed characterization of the formation and reactivity of various iron-peroxo- and iron-oxo intermediates that are involved in catalysis. Rates of rapid reactions were studied at low temperatures by a specialized technique termed cryogenic stopped-flow spectrophotometry. These measurements identified reaction conditions which favor the formation of catalytically competent oxidants. Chemical structures of reactive complexes was determined, and new, efficient catalysts for hydrocarbon oxidation were synthesized. Importantly, these catalysts are selective, they promote oxidation of hydrocarbons at a specific site. The catalysts are also efficient and robust, hundreds of cycles of substrate oxidation occur within minutes at room temperature. Furthermore, they enable utilization of environmentally friendly oxidants, such as hydrogen peroxide, which produces water as the only byproduct. Mechanistic insights uncovered the role of various acid-containing additives in catalytic oxidations. Proton delivery to the active catalytic sites facilitated oxidations, similarly to the catalytic pathways in metal-containing enzymes. Under certain conditions, two metals in one complex can act in concert, modeling the reactivity of a bacterial enzyme which converts methane into methanol. In related studies, a family of nickel complexes that react with carbon dioxide at the rates comparable to enzyme carbonic anhydrase, was discovered. Sequestration and chemical utilization of carbon dioxide is one of the important goals in energy production.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Structural and dynamical rationale for fatty acid unsaturation in Escherichia coli

Fatty acid biosynthesis in α- and γ-proteobacteria requires two functionally distinct dehydratases, FabA and FabZ. In this work, mechanistic cross-linking facilitates the structural characterization of a stable hexameric complex of six Escherichia coli FabZ dehydratase subunits with six AcpP acyl carrier proteins. The crystal structure sheds light on the divergent substrate selectivity of FabA and FabZ by revealing distinct architectures of the binding pocket. Molecular dynamics simulations demonstrate differential biasing of substrate orientations and conformations within the active sites of FabA and FabZ such that FabZ is preorganized to catalyze only dehydration, while FabA is primed for both dehydration and isomerization.

59 BASIC BIOLOGICAL SCIENCES↗

Catalytic polymer processing

A method of upcycling polymers to useful hydrocarbon materials. A catalyst with nanoparticles on a substrate selectively docks and cleaves longer hydrocarbon chains over shorter hydrocarbon chains. The catalyst includes metal nanoparticles in an order array on a substrate.

Delferro, Massimiliano↗

Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2

Abstract PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2’s U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3 BD2 . Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases.

Science & Technology - Other Topics↗

Insight into subtilisin E-S7 cleavage pattern based on crystal structure and hydrolysates peptide analysis

The X-ray crystallographic structure of the mature form of subtilisin E-S7 (SES7) at 1.90 Å resolution is reported in this paper. Structural comparisons between the previously reported propeptide-subtilisin E complex (1SCJ) and our mature form subtilisin E-S7 (6O44) provide insight into active site adjustments involved in catalysis and specificity. To further investigate the protease substrate selectivity mechanism, we used SES7 to hydrolyze skim milk and analyzed the hydrolysates by LC-MS for peptide identification. The cleavage pattern suggests a high preference for proline at substrate P2 position. The results based on the peptide analysis are consistent with our structural observations, which is instrumental in future protein engineering by rational design. Furthermore, the ACE-inhibitor and NLN-inhibitor activity of the hydrolysates were determined to assess the utility of SES7 for further industrial applications; IC50-ACE = 67 ± 0.92 μg/mL and IC50-NLN = 263 ± 13 μg/mL.

59 BASIC BIOLOGICAL SCIENCES↗

Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic

Abstract The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics. Organoarsenicals have been used as antimicrobials since Paul Ehrlich’s salvarsan. Recently a soil bacterium was shown to produce the organoarsenical arsinothricin. We demonstrate that arsinothricin, a non-proteinogenic analog of glutamate that inhibits glutamine synthetase, is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria, suggesting that bacteria have evolved the ability to utilize the pervasive environmental toxic metalloid arsenic to produce a potent antimicrobial. With every new antibiotic, resistance inevitably arises. The arsN1 gene, widely distributed in bacterial arsenic resistance ( ars ) operons, selectively confers resistance to arsinothricin by acetylation of the α-amino group. Crystal structures of ArsN1 N -acetyltransferase, with or without arsinothricin, shed light on the mechanism of its substrate selectivity. These findings have the potential for development of a new class of organoarsenical antimicrobials and ArsN1 inhibitors.

59 BASIC BIOLOGICAL SCIENCES↗

AM metal substrates for inkjet-printing of smart devices

Highlights: • An experimental study to characterize 3D-printed metal substrates and their surfaces for inkjet-printing is presented. • Multilayer structures composed of an insulating layer and a superposed conductive layer, inkjet-printed onto various metallic substrates. • Characterization based on microscopic and Focused Ion Beam (FIB) images, profilometer and contact angle measurements of the substrates. • Microscopic images and four-point-probe resistance- and profilometer measurements to gain insight into the quality of the multilayer print. - Abstract: A study to characterize surface and structural properties of 3D-printed metal substrates for multilayer inkjet-printing is presented. Such substrates can enable and alleviate the fabrication of smart and functional packages, implants or spare parts. For the characterization, a multilayer structure composed of an insulating layer and a superposed conductive layer is inkjet-printed onto the various 3D-printed metallic substrates. The printing is done using equivalent settings for all substrates. The characterization is based on microscopic and Focused Ion Beam (FIB) images, as well as profilometer and contact angle measurements of the substrates. Furthermore, microscopic images and four-point-probe resistance- and profilometer measurements are carried out, to gain insight into the quality of the multilayer print. We show the diversity in surface and structural properties of 3D-printed substrates, also for those fabricated using the same process. Also, the 3D-printed samples exhibit different wettability properties than metals processed using standard processes. Finally, we can also demonstrate the suitability of selected substrates for inkjet-printing.

36 MATERIALS SCIENCE↗

Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone

Cytochromes P450 (CYPs) form one of the largest enzyme superfamilies, with similar structural folds yet biological functions varying from synthesis of physiologically essential compounds to metabolism of myriad xenobiotics. Sterol 14α-demethylases (CYP51s) represent a very special P450 family, regarded as a possible evolutionary progenitor for all currently existing P450s. In metazoans CYP51 is critical for the biosynthesis of sterols including cholesterol. Here we determined the crystal structures of ligand-free CYP51s from the abyssal fish Coryphaenoides armatus and human-. Comparative sequence–structure–function analysis revealed specific structural elements that imply elevated conformational flexibility, uncovering a molecular basis for faster catalytic rates, lower substrate selectivity, and intrinsic resistance to inhibition. In addition, the C. armatus structure displayed a large-scale repositioning of structural segments that, in vivo, are immersed in the endoplasmic reticulum membrane and border the substrate entrance (the FG arm, >20 Å, and the β4 hairpin, >15 Å). The structural distinction of C. armatus CYP51, which is the first structurally characterized deep sea P450, suggests stronger involvement of the membrane environment in regulation of the enzyme function. We interpret this as a co-adaptation of the membrane protein structure with membrane lipid composition during evolutionary incursion to life in the deep sea.

Biochemistry & Molecular Biology↗

Critical Role of Surface Energy in Guiding Crystallization of Solution-Coated Conjugated Polymer Thin Films

It is well-known that substrate surface properties have a profound impact on morphology of thin films solution coated atop and the resulting solid-state properties. However, design rules for guiding the substrate selection have not yet been established. Such design rules are particularly important for solution coated semiconducting polymers, as the substratedirected thin film morphology can impact charge transport properties by orders of magnitude. We hypothesize that substrate surface energies dictate the thin film morphology by modulating the free energy barrier to heterogeneous nucleation. To test this hypothesis, we systematically vary the substrate surface energy via surface functionalization techniques. We perform in-depth morphology and device characterizations to establish the relationship between substrate surface energy, thin film morphology and charge transport properties, employing a donor-accepter (D-A) conjugated polymer. Here, we find that decreasing the substrate surface energy progressively increases thin film crystallinity, degree of molecular ordering and extent of domain alignment. Notably, the enhanced morphology on the lowest surface energy substrate lead to a 10-fold increase in the charge carrier mobility. We further develop a free energy model relating the substrate surface energy to the penalty of heterogeneous nucleation from solution in the thin film geometry. The model correctly predicts the experimental trend, thereby validating our hypothesis. This work is a significant step towards establishing design rules and understanding the critical role of substrates in determining morphology of solution coated thin films.

36 MATERIALS SCIENCE↗

Improved GaSb-based quantum well laser performance through metamorphic growth on GaAs substrates

The promise of the metamorphic growth paradigm is to enable design freedom of the substrate selection criteria beyond current choices that are limited by lattice matching requirements. A demonstration of this emerging degree of freedom is reported here by directly comparing identical laser structures grown both pseudomorphically on a GaSb substrate and metamorphically on a GaAs substrate. Improved thermal performance of the metamorphic laser material enables a higher output power before thermal roll-over begins. These performance gains are demonstrated in minimally processed gain-guided broad-area type-I lasers emitting close to 2-μm wavelengths and mounted p-side up. Continuous wave measurements at room temperature yield a T{sub 0} of 145 K and peak output power of 192 mW from metamorphic lasers, compared to a T{sub 0} of 96 K and peak output power of 164 mW from identical lasers grown pseudomorphically on GaSb.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

Bifunctional Heterometallic Metal-Organic Frameworks for Solvent-Free Heterogeneous Cascade Catalysis

A family of heterometallic metal-organic frameworks (MOFs) (CPM200s) harmoniously coexisting as Lewis acids and base (azo) sites were prepared. Seven CPM200s were employed as multifunctional heterogeneous cascade catalysts for the one-pot deacetalization-Knoevenagel reaction in a solvent-free system. Benefiting from the cooperation between Lewis acids from the open metal sites and base sites from the ligands, the CPM200s showed high activity and selectivity for the tandem reaction. The heterometallic 3D porous framework reported here not only offers a combination of two opposite active sites in the same framework of materials but also increases mass transfer of the substrate, thus maximizing the efficiency and substrate selectivity of the bifunctional catalysts. The CPM200s showed the highest turnover frequency (TOF), outperforming that of the reported MOFs in tandem with the deacetalization-Knoevenagel reaction. A strong correlation between the TOF and charge-to-radius ratio (z/r) of metal ions in the CPM200s was observed for the first time. The bifunctional CPM200s catalysts can be reused five times without significant loss of activity.

36 MATERIALS SCIENCE↗

Structural basis of promiscuous substrate transport by Organic Cation Transporter 1

Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Structural Basis of the Enhanced Pollutant-Degrading Capabilities of an Engineered Biphenyl Dioxygenase

Biphenyl dioxygenase, the first enzyme of the biphenyl catabolic pathway, is a major determinant of which polychlorinated biphenyl (PCB) congeners are metabolized by a given bacterial strain. Ongoing efforts aim to engineer BphAE, the oxygenase component of the enzyme, to efficiently transform a wider range of congeners. BphAE II9 , a variant of BphAE LB400 in which a seven-residue segment, 335 TFNNIRI 341 , has been replaced by the corresponding segment of BphAE B356 , 333 GINTIRT 339 , transforms a broader range of PCB congeners than does either BphAE LB400 or BphAE B356 , including 2,6-dichlorobiphenyl, 3,3'-dichlorobiphenyl, 4,4'-dichlorobiphenyl, and 2,3,4'-trichlorobiphenyl. To understand the structural basis of the enhanced activity of BphAE II9 , we have determined the three-dimensional structure of this variant in substrate-free and biphenyl-bound forms. Structural comparison with BphAE LB400 reveals a flexible active-site mouth and a relaxed substrate binding pocket in BphAE II9 that allow it to bind different congeners and which could be responsible for the enzyme's altered specificity. Biochemical experiments revealed that BphAE II9 transformed 2,3,4'-trichlorobiphenyl and 2,2',5,5'-tetrachlorobiphenyl more efficiently than did BphAE LB400 and BphAE B356 . BphAE II9 also transformed the insecticide dichlorodiphenyltrichloroethane (DDT) more efficiently than did either parental enzyme (apparent k cat /K m of 2.2 ± 0.5 mM –1 s –1 , versus 0.9 ± 0.5 mM –1 s –1 for BphAE B356 ). Studies of docking of the enzymes with these three substrates provide insight into the structural basis of the different substrate selectivities and regiospecificities of the enzymes. Biphenyl dioxygenase is the first enzyme of the biphenyl degradation pathway that is involved in the degradation of polychlorinated biphenyls. Attempts have been made to identify the residues that influence the enzyme activity for the range of substrates among various species. In this study, we have done a structural study of one variant of this enzyme that was produced by family shuffling of genes from two different species. Comparison of the structure of this variant with those of the parent enzymes provided an important insight into the molecular basis for the broader substrate preference of this enzyme. Here, the structural and functional details gained in this study can be utilized to further engineer desired enzymatic activity, producing more potent enzymes.

59 BASIC BIOLOGICAL SCIENCES↗

The structural basis of promiscuity in small multidrug resistance transporters

By providing broad resistance to environmental biocides, transporters from the small multidrug resistance (SMR) family drive the spread of multidrug resistance cassettes among bacterial populations. A fundamental understanding of substrate selectivity by SMR transporters is needed to identify the types of selective pressures that contribute to this process. Using solid-supported membrane electrophysiology, we find that promiscuous transport of hydrophobic substituted cations is a general feature of SMR transporters. To understand the molecular basis for promiscuity, we solved X-ray crystal structures of a SMR transporter Gdx-Clo in complex with substrates to a maximum resolution of 2.3 Å. These structures confirm the family’s extremely rare dual topology architecture and reveal a cleft between two helices that provides accommodation in the membrane for the hydrophobic substituents of transported drug-like cations.

59 BASIC BIOLOGICAL SCIENCES↗