DFT Study on the Substituent Effect of Anticancer Picoline-Diazido-Pt(IV) Compounds

The geometric structure of azido Pt(IV) compounds containing picoline was calculated by using density functional theory(DFT) at the LSDA/SDD level. The ESP distribution shows the possible reaction sites of the compounds. In addition, the frequency calculation results assigned the infrared spectra of these compounds, and specified important stretching and bending vibrations. The HOMO-LUMO energy gaps of these compounds are also calculated to explain the charge transfer of the molecules. The distribution of Mulliken charges and natural atomic charges of these atoms is also calculated. Natural bond orbital(NBO) analysis explains the intramolecular interactions and their electron density.

Nonlinear optical single crystals for terahertz generation and detection

Nonlinear optical (NLO) single crystals with high quality are the pillars for the development of new devices that fulfil the demands of society. Nowadays, NLO single crystals are very attractive for the photonic applications particularly for terahertz (THz) photonics. The reason for their popularity is that these crystals can produce very powerful and ultra wideband THz waves due to their high nonlinear susceptibility. In this review paper, we deal with the challenges and progresses in the evolution of NLO single crystals for THz wave generation and detection. Here, we review the single crystal growth that how and by which method single crystal is grown. We summarize the structures, intermolecular and intramolecular interactions, their properties and how they generate and detect the THz waves. Widely used single crystals at present are DAST, BNA, OH1, amino acid-based single crystals, etc.

Intramolecular interactions enhance the potency of gallinamide A analogs against Trypanosoma cruzi

Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated potency of gallinamide A and 23 synthetic analogs against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogs at ~2Å. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π-π stacking interactions between the aromatic substituents at P1 ′ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1′ interacts with tryptophan-184. The P1-P1′ interactions had no effect on anti-cruzain activity whereas anti-T. cruzi potency increased by ~5-fold, likely due to an increase in solubility/permeability of the analogs.

A mutation associated with Charcot-Marie-Tooth disease enhances the formation of stable dynamin 2 complexes in cells

Mutations in dynamin 2 (DNM2) have been associated with two distinct motor disorders, Charcot-Marie-Tooth neuropathies (CMT) and centronuclear myopathy (CNM). The majority of these mutations are clustered in the pleckstrin homology domain (PHD) which engage in intramolecular interactions that suppress dynamin self-assembly and GTPase activation. CNM mutations in the PHD interferes with these intramolecular interactions, thereby blocking the formation of the auto-inhibited state. CMT mutations are located primarily on the opposite surface of the PHD, which is specialized for lipid PIP2 binding. It has been speculated that the distinct locations and interactions of residues mutated in CMT and CNM explain why each set of mutations cause either one disease or the other, despite their close proximity within the PHD sequence. We show that at least one CMT-causing mutant, lacking residues 555DEE557 (∆DEE), displays this inability to undergo auto-inhibition as observed in CNM-linked mutants. This ∆DEE deletion mutant induces the formation of abnormally large cytoplasmic inclusions similar to those observed for CNM-linked mutant R369W. We also found substantially reduced migration from the membrane of the ∆DEE deletion mutant. These findings call into question the molecular mechanism currently believed to underlie the absence of pathogenic overlap between DNM2-dependent CMT and CNM.

SGT1 SGS-domain mutations impair interactions with the barley MLA6 immune receptor in association with loss of NLR protein

The Mla (Mildew resistance locus a) of barley (Hordeum vulgare L.) is an effective model for cereal immunity against fungal pathogens. Like many resistance proteins, variants of the MLA coiled-coil nucleotide-binding leucine-rich-repeat (CC-NLR) receptor require the HRS complex to function, which includes HSP90 (Heat Shock Protein 90), RAR1 (Required for Mla12 Resistance 1), and SGT1 (Suppressor of G-two allele of Skp1). However, functional analysis of Sgt1 has been particularly difficult as deletions are often lethal. Recently, we identified rar3 (Required for Mla6 resistance 3), an in-frame Sgt1ΔKL308-309 mutation in the SGS domain that alters resistance conferred by MLA, but without lethality. Here we use autoactive MLA6 and heterologous yeast-two-hybrid strains with stably integrated HvRar1 and HvHsp90, to determine that this mutation weakens, but doesn’t entirely disrupt, the interaction between SGT1 and MLA. This causes a concomitant reduction in MLA6 protein accumulation below the apparent threshold required for effective resistance. The ΔKL308-309 deletion had a lesser effect on intramolecular interactions than alanine or arginine substitutions, and MLA variants that display diminished interactions with SGT1 appear to be disproportionately affected by the SGT1ΔKL308-309 mutation. We hypothesize that those dimeric plant CC-NLRs that appear unaffected by Sgt1 silencing are those with the strongest intermolecular interactions with it. Combining our data with recent work in CC-NLRs, we propose a cyclical model of the MLA-HRS resistosome interactions.

1H, 13C and 15N resonance assignment of the SARS-CoV-2 full-length nsp1 protein and its mutants reveals its unique secondary structure features in solution

Structural characterization of the SARS-CoV-2 full length nsp1 protein will be an essential tool for developing new target-directed antiviral drugs against SARS-CoV-2 and for further understanding of intra- and intermolecular interactions of this protein. As a first step in the NMR studies of the protein, we report the 1H, 13C and 15N resonance backbone assignment as well as the Cβ of the apo form of the full-lengthSARS-CoV-2 nsp1 including the folded domain together with the flaking N- and C- terminal intrinsically disordered fragments. The 19.8 kD protein was characterized by high-resolution NMR. Validation of assignment have been done by using two different mutants, H81P and K129E/D48E as well as by amino acid specific experiments. According to the obtained assignment, the secondary structure of the folded domain in solution was almost identical to its previously published X-ray structure as well as another published secondary structure obtained by NMR, but some discrepancies have been detected. In the solution SARS-CoV-2 nsp1 exhibited disordered, flexible N- and C-termini with different dynamic characteristics. The short peptide in the beginning of the disordered C-terminal domain adopted two different conformations distinguishable on the NMR time scale. We propose that the disordered and folded nsp1 domains are not fully independent units but are rather involved in intramolecular interactions. Studies of the structure and dynamics of the SARS-CoV-2 mutant in solution are on-going and will provide important insights into the molecular mechanisms underlying these interactions.

The PNUTS-PAD domain recruits MYC to the PNUTS:PP1 phosphatase complex via the oncogenic MYC-MB0 region

SummaryDespite MYC dysregulation in most human cancers, strategies to target this potent oncogenic driver remains an urgent unmet need. Recent evidence shows the PP1 phosphatase and its regulatory subunit PNUTS control MYC phosphorylation and stability, however the molecular basis remains unclear. Here we demonstrate that MYC interacts directly with PNUTS through the MYC homology Box 0 (MB0), a highly conserved region recently shown to be important for MYC oncogenic activity. MB0 interacts with PNUTS residues 1-148, a functional unit here termed, PNUTS amino-terminal domain (PAD). Using NMR spectroscopy we determined the solution structure of PAD, and characterised its interaction with MYC. Point mutations of residues at the MYC-PNUTS interface significantly weaken their interaction both in vitro and in vivo. These data demonstrate the MB0 binding pocket of the PAD represents an attractive site for pharmacological disruption of the MYC-PNUTS interaction.In BriefSolving the structure of MYC-PNUTS direct interaction reveals how the intrinsically disordered MYC-Box0 (MB0) region anchors into a binding pocket in the N-terminal PAD domain of PNUTS. These data provide insight into the molecular mechanism of how the PNUTS:PP1 phosphatase complex regulates MYC phosphorylation.HighlightsA region critical for MYC oncogenesis, MYC-Box0 (MB0), directly interacts with PNUTSPNUTS amino-terminal domain (PAD) is a structural domain that interacts with MYC MB0Mutation of single residues at the interaction interface disrupts MYC-PNUTS binding in cellsMYC-PNUTS binding releases MYC intramolecular interactions to enable PP1substrate access

A teamwork promotion of formin-mediated actin nucleation by Bud6 and Aip5 in Saccharomyces cerevisiae

Actin nucleation is achieved by collaborative teamwork of actin nucleator factors (NFs) and nucleation-promoting factors (NPFs) into functional protein complexes. Selective inter- and intramolecular interactions between the nucleation complex constituents enable diverse modes of complex assembly in initiating actin polymerization upon demand. Budding yeast has two formins, Bni1 and Bnr1, which are teamed up with different NPFs. However, the selective pairing between formin NFs and NPFs into the nucleation core for actin polymerization is not completely understood. By examining the functions and interactions of NPFs and NFs via biochemistry, genetics, and mathematical modeling approaches, we found that two NPFs, Aip5 and Bud6, showed joint teamwork effort with Bni1 and Bnr1, respectively, by interacting with the C-terminal intrinsically disordered region (IDR) of formin, in which two NPFs work together to promote formin-mediated actin nucleation. Although the C-terminal IDRs of Bni1 and Bnr1 are distinct in length, each formin IDR orchestrates the recruitment of Bud6 and Aip5 cooperatively by different positioning strategies to form a functional complex. Our study demonstrated the dynamic assembly of the actin nucleation complex by recruiting multiple partners in budding yeast, which may be a general feature for effective actin nucleation by formins. [Media: see text]