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Conserved Binding Sites

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...

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Related Experiment Video

Updated: Apr 16, 2026

Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library

Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library

Published on: January 14, 2020

DNA-Encoded Library (DEL) Selection Identifies a Distinct DDB1 Ligand Binding Site.

Shiva Krishna Reddy Guduru¹, John P Caldwell¹, Katherine M Digianantonio¹

¹Arvinas, Inc., New Haven, Connecticut 06511, United States.

ACS Medicinal Chemistry Letters

|April 15, 2026

Summary

This summary is machine-generated.

Researchers developed novel DDB1 ligands for proteolysis targeting chimeras (PROTACs). This expands options beyond CRBN and VHL E3 ligases, advancing targeted protein degradation drug discovery.

Keywords:

DNA damage-binding protein 1 (DDB1)DNA-encoded library (DEL)E3 ubiquitin ligase X-ray crystallography ligand discovery structure-based drug design

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Last Updated: Apr 16, 2026

Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library

Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library

Published on: January 14, 2020

Primer-Free Aptamer Selection Using A Random DNA Library

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Published on: July 26, 2010

Identifying the Binding Proteins of Small Ligands with the Differential Radial Capillary Action of Ligand Assay DRaCALA

Identifying the Binding Proteins of Small Ligands with the Differential Radial Capillary Action of Ligand Assay DRaCALA

Published on: March 19, 2021

Area of Science:

Biochemistry
Medicinal Chemistry
Molecular Biology

Background:

Proteolysis targeting chimeras (PROTACs) are an emerging therapeutic modality for targeted protein degradation.
Current PROTACs predominantly utilize cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligase ligands.
There is a significant need for novel E3 ligase ligands to expand the scope of PROTAC technology.

Purpose of the Study:

To establish DDB1 as a viable E3 ligase adapter for PROTAC development.
To identify novel DDB1 ligands using a DNA-encoded library (DEL) approach.
To optimize initial DEL hits into potent DDB1 ligands.

Main Methods:

DNA-encoded library (DEL) screening for DDB1 ligand discovery.
Structure-guided medicinal chemistry for ligand optimization.
Biochemical assays, cellular target engagement studies, and X-ray crystallography for characterization.

Main Results:

Identification of a novel DDB1 ligand from a DEL campaign.
Optimization of DEL hits to achieve nanomolar potency.
Demonstration of ligand binding to a unique pocket in DDB1 via structural and biochemical analyses.

Conclusions:

DDB1 can be effectively utilized as an E3 ligase adapter for PROTAC drug discovery.
The identified DDB1 ligands represent a new chemical series with therapeutic potential.
This work expands the toolbox of small molecules for PROTAC development, offering alternatives to CRBN and VHL ligands.