Affinity-selected peptide ligands specifically bind i-motif DNA and modulate c-Myc gene expression

Abstract. c-Myc is an oncogene that is dysregulated in ∼70% of cancers. Its multifaceted function complicates effective drug targeting of the protein. i-Mo

academic.oup.com

FormatMyPaper - The End of Manuscript Formatting

Paste your paper, choose your journal, and let our AI handle the tedious rest. Get back to the science.

formatmypaper.com

Huntington's disease successfully treated for first time

One of the most devastating diseases finally has a treatment that can slow its progression and transform lives, tearful doctors tell BBC.

bbc.co.uk

DNA-Programmable Protein Degradation: Dynamic Control of Proteolysis-Targeting Chimera Activity via DNA Hybridization and Strand Displacement

Targeted protein degradation is a powerful therapeutic approach: expanding the druggable proteome, providing enhanced selectivity, and having the ability to overcome conventional resistance mechanisms...

pubs.acs.org

onlinelibrary.wiley.com

RNA: Searching for druggable targets

A strategy that analyzes the structural properties of RNA could help identify regions that are promising targets for antiviral drugs.

elifesciences.org

UK finally unveils £54 million global talent scheme

Much-anticipated package for recruiting foreign researchers follows similar moves by France and the European Union to snap up US scientists

timeshighereducation.com

Insights into the Enhanced Ceftazidime Hydrolysis by Ent385 AmpC β-Lactamase from Multiscale Simulations

The emergence of multidrug-resistant bacteria poses a significant threat to public health. Particularly, they are becoming increasingly resistant to β-lactam antibiotics, which are one of the most important drug classes for the treatment of bacterial infections. Ceftazidime-avibactam has shown promising activity against highly drug-resistant bacteria, including carbapenem-resistant Enterobacterales. However, an Ala294-Pro295 deletion in the Class CE. cloacaeAmpC β-lactamase can confer reduced susceptibility to these agents. In this study, we investigated the molecular mechanisms underlying the enhanced hydrolysis of ceftazidime by E. cloacae Ent385 AmpC β-lactamase with the deletion using quantum mechanics/molecular mechanics (QM/MM) simulations. We used constant pH molecular dynamics simulations of the β-lactamase-ceftazidime acyl-enzyme complex to verify the likely protonation states, confirming Tyr150 primarily exists as a tyrosinate. We then used QM/MM (DFTB2/ff14SB) umbrella sampling to calculate the reaction-free energy barriers (Δ‡G) for the deacylation step of cephalosporin hydrolysis. This reveals that Tyr150 (rather than the substrate) acts as the base. Importantly, the difference in Δ‡G between the canonical E. cloacae AmpC (P99) and the Ent385 variant with Ala294-Pro295 reinserted, on the one hand, and the Ent385 variant, on the other, was in very good agreement with the difference deduced from experimental kinetic data. Detailed analysis of the transition state ensembles, alongside additional simulations, shows that the Ala294-Pro295 deletion allows the entrance of an additional water molecule that helps stabilize the tetrahedral intermediate. Overall, our QM/MM simulations provide valuable insights into the reaction mechanism and reasons for enhanced ceftazidime breakdown. The protocol used in this study successfully captures the kinetic differences observed among the studied variants. This approach can be employed to investigate other Class C β-lactamase variants with similar features, providing insights into their mechanisms and potential contributions to reduced susceptibility to antibiotic treatments.

pubs.acs.org

Conformational Landscape of the Di- and Tripeptide Permease A Transport Cycle

Dipeptide and tripeptide permease A (DtpA) transporter is a bacterial homologue of the human PepT that is responsible for the uptake of di- and tripeptides from the small intestine and transports them...

pubs.acs.org

SAND: a comprehensive annotation of class D β-lactamases using structural alignment-based numbering | Antimicrobial Agents and Chemotherapy

Class D β-lactamases (DBLs) form a large family with nearly 1,300 identified members in the β-Lactamase Database (Fig. S1, www.bldb.euhttp://www.bldb.eu/) (1). They are produced mainly by Gram-negative bacteria, with some by Gram-positive bacteria (2). DBLs are an important mechanism of resistance to β-lactam antibiotics, including carbapenems, one of last resort treatments to infections in hospitalized patients (3). The production of class D β-lactamases is a major public health concern, as they can often transfer between different bacterial species, allowing resistance to spread quickly and widely. Some members were found to be membrane-bound and are secreted via outer membrane vesicles (OMVs) to contribute further in antimicrobial resistance dissemination (4). Their mechanism of action involves a catalytic serine, as in classes A and C β-lactamases, since all share the conserved SXXK tetrad and KXG triad (3).

journals.asm.org

Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9)

Glucose transporters (GLUTs) play critical roles in cellular energy homeostasis and substrate-specific transport. Dysfunctional mutations can cause GLUT1 deficiency syndrome, and excessive expression ...

pubs.acs.org