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Ligand Binding Sites

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...

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Updated: Mar 23, 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

Discovery of Ultrapotent Heterodimeric Peptide Ligands Using Library-vs-Library RaPID Selections.

Yuto Ohno¹, Alexander A Vinogradov^1,2, Hiroaki Suga¹

¹Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

Journal of the American Chemical Society

|March 17, 2026

Summary

This summary is machine-generated.

Researchers developed a novel platform to discover functional peptide pairs, identifying an ultra-potent heterodimeric ligand for 14-3-3ζ protein. This method accelerates drug discovery for challenging protein targets.

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Published on: December 1, 2020

Area of Science:

Biochemistry
Molecular Biology
Drug Discovery

Background:

Identifying functional peptide pairs is challenging.
Combinatorial peptide libraries offer vast chemical spaces for ligand discovery.
Existing methods for discovering peptide pairs are limited.

Purpose of the Study:

To develop a library-vs-library in vitro selection platform for discovering heterodimeric macrocyclic peptide ligands.
To demonstrate the platform's utility by identifying a potent ligand for 14-3-3ζ protein.

Main Methods:

Utilized the Random nonstandard Peptides Integrated Discovery (RaPID) system.
Employed protein-templated ligation of peptides from two mRNA display libraries.
Selected for functional heterodimers based on binding to the target protein.

Main Results:

Developed a novel platform for heterodimeric peptide ligand discovery.
Identified an ultrapotent heterodimeric ligand (h1.2) for 14-3-3ζ protein with a K_D of 120 pM.
Demonstrated accelerated formation and superior affinity of the heterodimer compared to individual monomers.

Conclusions:

The developed platform enables the discovery of high-affinity heterodimeric ligands.
This strategy is applicable for targeting oligomeric proteins, proteins lacking binding pockets, and disrupting protein-protein interactions.
The method holds promise for advancing drug discovery efforts.