Structural basis for a shared mode of action between a pair of corn rootworm actives from a Bacillus thuringienses and a non-Bacillusbacterial source

2016 ◽  
Author(s):  
Nasser Yalpani
Keyword(s):  
Mode Of Action ◽  
Structural Basis ◽  
Corn Rootworm

scholarly journals Evaluating Iso-Mukaadial Acetate and Ursolic Acid Acetate as Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase Inhibitors

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 861
Author(s):  
Francis Opoku ◽  
Penny P. Govender ◽  
Ofentse J. Pooe ◽  
Mthokozisi B.C. Simelane
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Ursolic Acid ◽  
Mode Of Action ◽  
In Silico ◽  
Structural Basis ◽  
Depth Information ◽  
Dependent Manner ◽  
High Affinity ◽  
Molecular Docking And Dynamics

To date, Plasmodium falciparum is one of the most lethal strains of the malaria parasite. P. falciparum lacks the required enzymes to create its own purines via the de novo pathway, thereby making Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPT) a crucial enzyme in the malaria life cycle. Recently, studies have described iso-mukaadial acetate and ursolic acid acetate as promising antimalarials. However, the mode of action is still unknown, thus, the current study sought to investigate the selective inhibitory and binding actions of iso-mukaadial acetate and ursolic acid acetate against recombinant PfHGXPT using in-silico and experimental approaches. Recombinant PfHGXPT protein was expressed using E. coli BL21 cells and homogeneously purified by affinity chromatography. Experimentally, iso-mukaadial acetate and ursolic acid acetate, respectively, demonstrated direct inhibitory activity towards PfHGXPT in a dose-dependent manner. The binding affinity of iso-mukaadial acetate and ursolic acid acetate on the PfHGXPT dissociation constant (KD), where it was found that 0.0833 µM and 2.8396 µM, respectively, are indicative of strong binding. The mode of action for the observed antimalarial activity was further established by a molecular docking study. The molecular docking and dynamics simulations show specific interactions and high affinity within the binding pocket of Plasmodium falciparum and human hypoxanthine-guanine phosphoribosyl transferases. The predicted in silico absorption, distribution, metabolism and excretion/toxicity (ADME/T) properties predicted that the iso-mukaadial acetate ligand may follow the criteria for orally active drugs. The theoretical calculation derived from ADME, molecular docking and dynamics provide in-depth information into the structural basis, specific bonding and non-bonding interactions governing the inhibition of malarial. Taken together, these findings provide a basis for the recommendation of iso-mukaadial acetate and ursolic acid acetate as high-affinity ligands and drug candidates against PfHGXPT.

scholarly journals Crystal structure of Arabidopsis thaliana HPPK/DHPS, a bifunctional enzyme and target of the herbicide asulam

2021 ◽  
Author(s):  
Grishma Vadlamani ◽  
Kirill V Sukhoverkov ◽  
Joel Haywood ◽  
Karen J Breese ◽  
Mark F Fisher ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Arabidopsis Thaliana ◽  
Mode Of Action ◽  
Rational Design ◽  
Binding Pocket ◽  
Structural Basis ◽  
Metabolic Resistance ◽  
Folate Biosynthesis ◽  
Limited Opportunity ◽  
Regulatory Scrutiny

Herbicides are vital for modern agriculture, but their utility is threatened by genetic or metabolic resistance in weeds as well as heightened regulatory scrutiny. Of the known herbicide modes of action, 6-hydroxymethyl-7,8-dihydropterin synthase (DHPS) which is involved in folate biosynthesis, is targeted by just one commercial herbicide, asulam. A mimic of the substrate para-aminobenzoic acid, asulam is chemically similar to sulfonamide antibiotics - and while still in widespread use, asulam has faced regulatory scrutiny. With an entire mode of action represented by just one commercial agrochemical, we sought to improve the understanding of its plant target. Here we solve a 2.6 Å resolution crystal structure for Arabidopsis thaliana DHPS that is conjoined to 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and reveal a strong structural conservation with bacterial counterparts at the sulfonamide-binding pocket of DHPS. We demonstrate asulam and the antibiotics sulfacetamide and sulfamethoxazole have herbicidal as well as antibacterial activity and explore the structural basis of their potency by modelling these compounds in mitochondrial HPPK/DHPS. Our findings suggest limited opportunity for the rational design of plant selectivity from asulam and that pharmacokinetic or delivery differences between plants and microbes might be the best approaches to safeguard this mode of action.

scholarly journals Small Molecule HIV-1 Attachment Inhibitors: Discovery, Mode of Action and Structural Basis of Inhibition

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 843
Author(s):  
Yen-Ting Lai
Keyword(s):  
Viral Entry ◽  
Mode Of Action ◽  
Host Cells ◽  
Structural Basis ◽  
Structural Studies ◽  
Mechanistic Studies ◽  
Resistance Mutations ◽  
Inhibitor Discovery ◽  
Surface Envelope ◽  
Hiv 1

Viral entry into host cells is a critical step in the viral life cycle. HIV-1 entry is mediated by the sole surface envelope glycoprotein Env and is initiated by the interaction between Env and the host receptor CD4. This interaction, referred to as the attachment step, has long been considered an attractive target for inhibitor discovery and development. Fostemsavir, recently approved by the FDA, represents the first-in-class drug in the attachment inhibitor class. This review focuses on the discovery of temsavir (the active compound of fostemsavir) and analogs, mechanistic studies that elucidated the mode of action, and structural studies that revealed atomic details of the interaction between HIV-1 Env and attachment inhibitors. Challenges associated with emerging resistance mutations to the attachment inhibitors and the development of next-generation attachment inhibitors are also highlighted.

The Structural Basis for the Exo-mode of Action in GH74 Oligoxyloglucan Reducing End-specific Cellobiohydrolase

2007 ◽  
Vol 370 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Katsuro Yaoi ◽  
Hidemasa Kondo ◽  
Ayako Hiyoshi ◽  
Natsuko Noro ◽  
Hiroshi Sugimoto ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Structural Basis

scholarly journals Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

2021 ◽  
Author(s):  
Walther Mothes ◽  
Wenwei Li ◽  
Yaozong Chen ◽  
Jeremie Prevost ◽  
Irfan Ullah ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mode Of Action ◽  
Neutralizing Antibodies ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Immunogen ◽  
Immunogen Design

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the RBD-up position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among beta-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

scholarly journals Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

Cell Reports ◽  
2021 ◽  
pp. 110210
Author(s):  
Wenwei Li ◽  
Yaozong Chen ◽  
Jérémie Prévost ◽  
Irfan Ullah ◽  
Maolin Lu ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Neutralizing Antibodies ◽  
Structural Basis ◽  
Broadly Neutralizing Antibodies

Effects of 5-5'-Diphenyl-2-thiohydantoin (DPTH) and Thyroxine on the Ultrastructure and Chemical Composition of Rat Liver

1971 ◽  
Vol 29 ◽  
pp. 570-571
Author(s):  
E. A. Elfont ◽  
R. B. Tobin ◽  
D. G. Colton ◽  
M. A. Mehlman
Keyword(s):  
Chemical Composition ◽  
Rat Liver ◽  
Future Study ◽  
Mode Of Action ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Effective Inhibitor ◽  
Biochemical Effects ◽  
Glycerophosphate Dehydrogenase ◽  
Stimulation Of

Summary5,-5'-diphenyl-2-thiohydantoin (DPTH) is an effective inhibitor of thyroxine (T4) stimulation of α-glycerophosphate dehydrogenase in rat liver mitochondria. Because this finding indicated a possible tool for future study of the mode of action of thyroxine, the ultrastructural and biochemical effects of DPTH and/or thyroxine on rat liver mere investigated.Rats were fed either standard or DPTH (0.06%) diet for 30 days before T4 (250 ug/kg/day) was injected. Injection of T4 occurred daily for 10 days prior to sacrifice. After removal of the liver and kidneys, part of the tissue was frozen at -50°C for later biocheailcal analyses, while the rest was prefixed in buffered 3.5X glutaraldehyde (390 mOs) and post-fixed in buffered 1Z OsO4 (376 mOs). Tissues were embedded in Araldlte 502 and the sections examined in a Zeiss EM 9S.Hepatocytes from hyperthyroid rats (Fig. 2) demonstrated enlarged and more numerous mitochondria than those of controls (Fig. 1). Glycogen was almost totally absent from the cytoplasm of the T4-treated rats.

Organization of tight junctions in the choroid plexus epithelium

1978 ◽  
Vol 36 (2) ◽  
pp. 336-337
Author(s):  
B. Van Deurs ◽  
J. K. Koehler
Keyword(s):  
Choroid Plexus ◽  
Present Report ◽  
Freeze Fracture ◽  
Barrier Properties ◽  
Cell Junctions ◽  
Structural Basis ◽  
Apical Surface ◽  
Choroid Plexus Epithelium ◽  
Solid Nitrogen ◽  
Special Composition

The choroid plexus epithelium constitutes a blood-cerebrospinal fluid (CSF) barrier, and is involved in regulation of the special composition of the CSF. The epithelium is provided with an ouabain-sensitive Na/K-pump located at the apical surface, actively pumping ions into the CSF. The choroid plexus epithelium has been described as “leaky” with a low transepithelial resistance, and a passive transepithelial flux following a paracellular route (intercellular spaces and cell junctions) also takes place. The present report describes the structural basis for these “barrier” properties of the choroid plexus epithelium as revealed by freeze fracture.Choroid plexus from the lateral, third and fourth ventricles of rats were used. The tissue was fixed in glutaraldehyde and stored in 30% glycerol. Freezing was performed either in liquid nitrogen-cooled Freon 22, or directly in a mixture of liquid and solid nitrogen prepared in a special vacuum chamber. The latter method was always used, and considered necessary, when preparations of complementary (double) replicas were made.

Sign in / Sign up

Export Citation Format

Share Document