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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.
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Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...

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Ligand Binding Sites

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Related Experiment Video

Updated: Jun 7, 2025

Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods

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Published on: December 21, 2019

Prediction of SHP2-E76K binding sites based on molecular dynamics simulation and Markov algorithm.

Si-Pei Zhang¹, Li-Juan Chen¹, Zhen-Liang Shi²

¹Department of Pharmacy, Tianjin Chest Hospital, Tianjin, China.

Journal of Biomolecular Structure & Dynamics

|November 19, 2024

Summary

This study reveals the dynamic binding of SHP099 to the SHP2-E76K mutant, crucial for targeting solid tumors. Understanding this interaction aids in developing more effective SHP2-E76K inhibitors.

Keywords:

MM/PBSA Markov model SHP2-E76K transition path theory umbrella sampling

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

The PTPN11 gene encodes SHP2, a protein phosphatase implicated in various solid tumors when mutated to SHP2-E76K.
SHP2-E76K is a promising drug target, yet effective inhibitors are currently unavailable.
While the static crystal structure of SHP099 with SHP2-E76K exists, its dynamic binding behavior remains uncharacterized.

Purpose of the Study:

To elucidate the dynamic interactions between the inhibitor SHP099 and the SHP2-E76K enzyme.
To identify the precise active binding site of SHP099 within SHP2-E76K at an atomistic level.
To provide insights for designing more potent SHP2-E76K inhibitors.

Main Methods:

Molecular dynamics (MD) simulations were employed to capture the dynamic behavior of the SHP099-SHP2-E76K complex.
Markov state modeling (MSM) was utilized to analyze the kinetic pathways of the inhibitor binding.
Atomistic details of the enzyme-inhibitor interaction were characterized.

Main Results:

The study characterized the kinetics of SHP099 binding to the SHP2-E76K active site.
Key atomistic interactions governing the enzyme-inhibitor complex were identified.
The dynamic binding process and active site interactions were revealed.

Conclusions:

This research provides a detailed dynamic understanding of SHP099 binding to SHP2-E76K.
The findings offer critical insights into enzyme-substrate interactions for SHP2-E76K.
The study lays the groundwork for the rational design of novel and more effective SHP2-E76K inhibitors.