Targeted degradation of Pin1 by protein-destabilizing compounds.

The concept of targeted protein degradation is at the forefront of modern drug discovery, which aims to eliminate disease-causing proteins using specific molecules. In this paper, we explored the idea to design protein degraders based on the section of ligands that cause protein destabilization, hence that facilitate the cellular breakdown of the target. Our studies present covalent agents targeting Pin1, a cis-trans prolyl isomerase that plays a crucial role in tumorigenesis.

Durability and Efficacy of Faricimab in Treatment-Resistant Retinal Edema Utilizing "Real-World" Dosing Regimens.

To retrospectively analyze clinical outcomes of patients with "treatment-resistant" neovascular age-related macular degeneration or diabetic macular edema who were switched to intravitreal faricimab injections (IFIs) using a "real-world" treat-and-extend (TAE) protocol. Seventy-one eyes from 62 patients receiving antivascular endothelial growth factor injections were evaluated before and after switching to IFI. Demographic and clinical data were collected.

Single-molecule tracking reveals dynamic regulation of ribosomal scanning.

How eukaryotic ribosomes traverse messenger RNA (mRNA) leader sequences to search for protein-synthesis start sites remains one of the most mysterious aspects of translation and its regulation. While the search process is conventionally described by a linear "scanning" model, its exquisitely dynamic nature has restricted detailed mechanistic study. Here, we observed single ribosomal scanning complexes in real time, finding that they scan diverse mRNA leaders at a rate of 10 to 20 nt s.

Structural basis of RfaH-mediated transcription-translation coupling.

The NusG paralog RfaH mediates bacterial transcription-translation coupling in genes that contain a DNA sequence element, termed an ops site, required for pausing RNA polymerase (RNAP) and for loading RfaH onto the paused RNAP. Here, we report cryo-electron microscopy structures of transcription-translation complexes (TTCs) containing Escherichia coli RfaH. The results show that RfaH bridges RNAP and the ribosome, with the RfaH N-terminal domain interacting with RNAP and the RfaH C-terminal domain interacting with the ribosome.

Structural basis of long-range transcription-translation coupling.

Structures recently have been reported of molecular assemblies that mediate transcription-translation coupling in . In these molecular assemblies, termed "coupled transcription-translation complexes" or "TTC-B", RNA polymerase (RNAP) interacts directly with the ribosome, the transcription elongation factor NusG or its paralog RfaH forms a bridge between RNAP and ribosome, and the transcription elongation factor NusA optionally forms a second bridge between RNAP and ribosome. Here, we have determined structures of coupled transcription-translation complexes having mRNA spacers between RNAP and ribosome longer than the maximum-length mRNA spacer compatible with formation of TTC-B.