Related Experiment Video

Updated: Aug 8, 2026

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

A molecular modeling study of inhibitors of nuclear factor kappa-B (p50)--DNA binding

Vineet Pande1, Rakesh K Sharma, Jun-Ichiro Inoue

  • 1REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.

Journal of Computer-Aided Molecular Design
|May 6, 2004
PubMed

Insights

This study identifies key structural features for inhibiting HIV-1 replication by targeting Nuclear Factor-kappa B (NF-kappaB) p50-DNA binding. Active inhibitors form strong hydrogen bonds and possess complementary electronegative surfaces for effective p50-DNA interaction.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Computational Chemistry

Background:

  • Nuclear Factor-kappa B (NF-kappaB) is crucial for viral replication, particularly HIV-1, by binding to its Long Terminal Repeat (LTR) DNA.
  • Inhibiting NF-kappaB p50-DNA binding offers a novel anti-HIV strategy to overcome drug resistance.
  • Understanding the structural mechanism of inhibitors is key to designing effective anti-HIV agents.

Purpose of the Study:

  • To define the common structural mechanism of NF-kappaB inhibitors targeting p50-DNA binding.
  • To identify key properties for novel lead compounds inhibiting p50-DNA binding.

Main Methods:

  • Molecular modeling and docking studies using GOLD were performed on three classes of inhibitors.
  • Molecular Electrostatic Potentials (MEPs) were generated to analyze electrostatic complementarity.
  • Inhibitors' association with the DNA-Binding Region (DBR) of the NF-kappaB p50 subunit was modeled.

Main Results:

  • Active inhibitors demonstrated a strong network of hydrogen bonding interactions with the p50 DBR.
  • Less active inhibitors showed a lack of significant hydrogen bonding.
  • MEPs indicated that the p50 DBR has an electropositive potential, and active inhibitors have a complementary electronegative surface.

Conclusions:

  • Effective inhibition of p50-DNA binding requires strong hydrogen bonding capabilities.
  • Ideal inhibitors should possess electronegative peripheral surfaces to complement the p50 DBR's electropositive potential.
  • These findings provide a basis for designing new anti-HIV gene expression inhibitors.

More Related Videos

Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO13:02

Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO

Published on: December 28, 2019

NF-κB-dependent Luciferase Activation and Quantification of Gene Expression in Salmonella Infected Tissue Culture Cells10:57

NF-κB-dependent Luciferase Activation and Quantification of Gene Expression in Salmonella Infected Tissue Culture Cells

Published on: January 12, 2020

Related Concept Videos

Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
Cooperative Binding of Transcription Regulators02:13

Cooperative Binding of Transcription Regulators

Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that...
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Cooperative Binding of Transcription Regulators02:13

Cooperative Binding of Transcription Regulators

Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that...