A PHP Error was encountered

Severity: Warning

Message: fopen(/var/lib/php/sessions/ci_sessionnjlf3h3f96mocbrgq70204a0sd27omas): Failed to open stream: No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 177

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once

A PHP Error was encountered

Severity: Warning

Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)

Filename: Session/Session.php

Line Number: 137

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once

Identification of small-molecule protein-protein interaction inhibitors for NKG2D. | LitMetric

AI Article Synopsis

  • NKG2D is a receptor that helps activate immune responses against infections and stress but can also contribute to chronic inflammation and autoimmune diseases, making it a target for new treatments.
  • The study outlines a strategy for identifying small molecules that can inhibit NKG2D's protein interactions via a unique mechanism that alters the receptor's structure.
  • Researchers used various biochemical methods and drug design techniques to enhance the effectiveness and properties of one series of inhibitors, showing it's feasible to disrupt the NKG2D interaction with its ligands through allosteric modulation.

Article Abstract

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ, and CD8 T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10160951PMC
http://dx.doi.org/10.1073/pnas.2216342120DOI Listing

Publication Analysis

Top Keywords

protein-protein interaction
8
interaction inhibitors
8
nkg2d
8
inhibitors nkg2d
8
identification small-molecule
4
small-molecule protein-protein
4
nkg2d nkg2d
4
nkg2d natural-killer
4
natural-killer group
4
group member
4

Similar Publications

G protein-coupled estrogen receptor 1 (GPER1) plays a crucial role in the progression of breast cancer and has emerged as a promising therapeutic target. However, while missense mutations in GPER1 have been detected in breast invasive carcinoma (BIC) samples, the resulting molecular, cellular and pharmacological changes remain unclear. The present study categorized BIC samples from The Cancer Genome Atlas database based on mutation information available in the cBioPortal database.

View Article and Find Full Text PDF

Sulfonium is an electrophilic and biocompatible group that is widely applied in synthetic chemistry on small molecules. However, there have been few developments of peptide or protein-based sulfonium tools. We recently reported sulfonium-mediated tryptophan crosslinking and developed NleSme2 (norleucine-dimethylsulfonium) peptides as dimethyllysine mimics that crosslink site-specific methyllysine readers.

View Article and Find Full Text PDF

Association between hypothyroidism and obstructive sleep apnea: a bidirectional Mendelian randomization study combined with the geo database.

Front Neurol

December 2024

Key Laboratory of Oral Diseases Research of Anhui Province, College & Hospital of Stomatology, Anhui Medical University, Hefei, China.

Background: The causal relationship between hypothyroidism and obstructive sleep apnea (OSA) remains controversial. Therefore, our research used a bidirectional Mendelian randomization (MR) method in an attempt to determine the causal relationship between hypothyroidism and OSA.

Methods: From the publicly accessible genome-wide association analysis (GWAS) summary database, we obtained single nucleotide polymorphism (SNPs) data pertaining to hypothyroidism and OSA.

View Article and Find Full Text PDF

Background: Periodontitis is among the most prevalent inflammatory conditions and greatly impacts oral health. This study aimed to elucidate the role of basement membrane-related genes in the pathogenesis and diagnosis of periodontitis.

Methods: GSE10334 was used for identification of hub genes via the differential analysis, protein-protein interaction network, MCC and DMNC algorithms, and evaluation via LASSO regression and support vector machine analysis to identify basement membrane-related markers in patients with periodontitis.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!