4,4′-Bipyridine–terephthalic acid (1/1)

The asymmetric unit of the title compound, C10H8N2·C8H6O4, consists of one half-mol­ecule of each moiety, 4,4′-bipyridine (bpy) and terephthalic acid (bdc), both being located on crystallographic inversion centers. They are linked together via strong inter­molecular O—H⋯N hydrogen bonds, forming infinite chains propagating along [1-21]. The chains are further connected through C—H⋯O inter­actions giving sheets in (012). The sheets are linked via π–π inter­actions between the bpy rings and the bdc–bpy rings [centroid–centroid distances = 3.690 (2) and 3.869 (2) Å], resulting in the formation of a three-dimensional supra­molecular layer-like structure

The structure of Toho1 β-lactamase in complex with penicillin reveals the role of Tyr105 in substrate recognition

The role of the conserved residue Tyr105 in class A β-lactamases has been the subject of investigation using both structural studies and saturation mutagenesis. Both have shown that while it does not need to be strictly conserved for activity, it is important for substrate recognition. With this in mind we determined the crystal structure of Toho1 β-lactamase at 15 K to 1.10 Å resolution in complex with penicillin. As expected a ring-opened penicillin molecule bound to Ser70 the catalytic nucleophile, can clearly be seen in electron density in the active site. In addition to the trapped penicillin, however, are two additional intact ring-closed penicillin molecules, captured by the enzyme through noncovalent interactions at the edge of the active site

Dimethyl­ammonium 3-carb­oxy­benzoate

The asymmetric unit of the title organic salt, C2H8N+·C8H5O4 −, consists of two dimethyl­ammonium cations and two 3-carb­oxy­benzoate anions. The 3-carb­oxy­benzoate anions are linked via strong inter­molecular and nearly symmetrical O—H⋯O hydrogen bonds forming infinite chains parallel to [111]. Neighbouring chains are further connected by the dimethyl­ammonium cations via N—H⋯O bonds, resulting in a double-chain-like structure. The dihedral angles of all carboxylate groups with respect to the phenylene rings are in the range 7.9 (1)–20.48 (9)°

A CASE REPORT ON DRUG INDUCED GYNACOMASTIA

Gynacomastia is a rare condition in males with a symptom of enlarged breast tissue size. It is generally caused by altered ratio of estrogens to androgens in the male individuals. A cause includes several diseases and nearly25% is associate with drugs. A mostly used drug that causes gynacomastia includes spironolactone, amlodepine, TCAs, and ketoconazole. It is a rare side effect. But it has a occurrence of 1% in amlodepine and 1.2% in spironolactone. Diagnosis is majorly done by presence of symptoms like increased breast tissue, and it should be differentiate with pseudo disease, and the increasing nature may be of one side or on both side of individuals. Presence of polactin secreting tumor may induce milk ejection from male breasts. Mostly it is resolved with in one to two months of discontinuation of suspected drug. Mastectomy is the only surgical procedure where the increased breast tissue is removed. Drugs like aromatase inhibitors, estrogen receptor modulators can also be used, but has no clinical practice in males

Active-site protonation states in an Acyl-Enzyme intermediate of a Class A β-Lactamase with a Monobactam Substrate

The monobactam antibiotic aztreonam is used to treat cystic fibrosis patients with chronic pulmonary infections colonized by Pseudomonas aeruginosa strains expressing CTX-M extended-spectrum β-lactamases. The protonation states of active-site residues that are responsible for hydrolysis have been determined previously for the apo form of a CTX-M β-lactamase but not for a monobactam acyl-enzyme intermediate. Here we used neutron and high-resolution X-ray crystallography to probe the mechanism by which CTX-M extended-spectrum β-lactamases hydrolyze monobactam antibiotics. In these first reported structures of a class A β-lactamase in an acyl-enzyme complex with aztreonam, we directly observed most of the hydrogen atoms (as deuterium) within the active site. Although Lys 234 is fully protonated in the acyl intermediate, we found that Lys 73 is neutral. These findings are consistent with Lys 73 being able to serve as a general base during the acylation part of the catalytic mechanism, as previously proposed

The use of hydrothermal methods in the synthesis of novel open-framework materials

The preparation of inorganic compounds, exhibiting open-framework structures, by hydrothermal methods has been presented. To illustrate the efficacy of this approach, few select examples encompassing a wide variety and diversity in the structures have been provided. In all the cases, good quality single crystals were obtained, which were used for the elucidation of the structure. In the first example, simple inorganic network compounds based on phosphite and arsenate are described. In the second example, inorganic-organic hybrid compounds involving phosphite/arsenate along with oxalate units are presented. In the third example, new coordination polymers with interesting structures are given. The examples presented are representative of the type and variety of compounds one can prepare by careful choice of the reaction conditions

The structure of a potassium-selective ion channel reveals a hydrophobic gate regulating ion permeation

Protein dynamics are essential to function. One example of this is the various gating mechanisms within ion channels, which are transmembrane proteins that act as gateways into the cell. Typical ion channels switch between an open and closed state via a conformational transition which is often triggered by an external stimulus, such as ligand binding or pH and voltage differences. The atomic resolution structure of a potassium-selective ion channel named NaK2K has allowed us to observe that a hydro­phobic residue at the bottom of the selectivity filter, Phe92, appears in dual conformations. One of the two conformations of Phe92 restricts the diameter of the exit pore around the selectivity filter, limiting ion flow through the channel, while the other conformation of Phe92 provides a larger-diameter exit pore from the selectivity filter. Thus, it can be concluded that Phe92 acts as a hydro­phobic gate, regulating the flow of ions through the selectivity filter

Comparative Structural and Computational Analysis Supports Eighteen Cellulose Synthases in the Plant Cellulose Synthesis Complex

A six-lobed membrane spanning cellulose synthesis complex (CSC) containing multiple cellulose synthase (CESA) glycosyltransferases mediates cellulose microfibril formation. The number of CESAs in the CSC has been debated for decades in light of changing estimates of the diameter of the smallest microfibril formed from the β-1,4 glucan chains synthesized by one CSC. We obtained more direct evidence through generating improved transmission electron microscopy (TEM) images and image averages of the rosette-type CSC, revealing the frequent triangularity and average cross-sectional area in the plasma membrane of its individual lobes. Trimeric oligomers of two alternative CESA computational models corresponded well with individual lobe geometry. A six-fold assembly of the trimeric computational oligomer had the lowest potential energy per monomer and was consistent with rosette CSC morphology. Negative stain TEM and image averaging showed the triangularity of a recombinant CESA cytosolic domain, consistent with previous modeling of its trimeric nature from small angle scattering (SAXS) data. Six trimeric SAXS models nearly filled the space below an average FF-TEM image of the rosette CSC. In summary, the multifaceted data support a rosette CSC with 18 CESAs that mediates the synthesis of a fundamental microfibril composed of 18 glucan chains

Bispecific killer cell engager with high affinity and specificity toward CD16a on NK cells for cancer immunotherapy

IntroductionThe Fc region of monoclonal antibodies (mAbs) interacts with the CD16a receptor on natural killer (NK) cells with “low affinity” and “low selectivity”. This low affinity/selectivity interaction results in not only suboptimal anticancer activity but also induction of adverse effects. CD16a on NK cells binds to the antibody-coated cells, leading to antibody-dependent cell-mediated cytotoxicity (ADCC). Recent clinical data have shown that the increased binding affinity between mAb Fc region and CD16a receptor is responsible for significantly improved therapeutic outcomes. Therefore, the objective of this study was to develop a bispecific killer cell engager (BiKE) with high affinity and specificity/selectivity toward CD16a receptor for NK cell-based cancer immunotherapy.MethodsTo engineer BiKE, a llama was immunized, then high binding anti-CD16a and anti-HER2 VHH clones were isolated using phage display. ELISA, flow cytometry, and biolayer interferometry (BLI) data showed that the isolated anti-CD16a VHH has high affinity (sub-nanomolar) toward CD16a antigen without cross-reactivity with CD16b-NA1 on neutrophils or CD32b on B cells. Similarly, the data showed that the isolated anti-HER2 VHH has high affinity/specificity toward HER2 antigen. Using a semi-flexible linker, anti-HER2 VHH was recombinantly fused with anti-CD16a VHH to create BiKE:HER2/CD16a. Then, the ability of BiKE:HER2/CD16a to activate NK cells to release cytokines and kill HER2+ cancer cells was measured. As effector cells, both high-affinity haNK92 (CD16+, V176) and low-affinity laNK92 (CD16+, F176) cells were used.Results and discussionThe data showed that the engineered BiKE:HER2/CD16a activates haNK92 and laNK92 cells to release cytokines much greater than best-in-class mAbs in the clinic. The cytotoxicity data also showed that the developed BiKE induces higher ADCC to both ovarian and breast cancer cells in comparison to Trazimera™ (trastuzumab). According to the BLI data, BiKE:HER2/CD16 recognizes a different epitope on CD16a antigen than IgG-based mAbs; thus, it provides the opportunity for not only monotherapy but also combination therapy with other antibody drugs such as checkpoint inhibitors and antibody-drug conjugates. Taken together, the data demonstrate the creation of a novel BiKE with high affinity and specificity toward CD16a on NK cells with the potential to elicit a superior therapeutic response in patients with HER2+ cancer than existing anti-HER2 mAbs