SH2 Domain Variants With Higher Phosphotyrosine Binding Affinity
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Solution Overview
Problem
Natural SH2 domains exhibit low binding affinity to phosphotyrosine (pTyr)-containing proteins, hindering effective targeting of protein phosphorylation pathways for therapeutic interventions.
Innovation Solution
Modified SH2 domains with specific amino acid substitutions in the BC loop region and C and D anti-parallel β-sheets, enhanced with hydrophobic interactions and hydrogen bonding, provide increased affinity for pTyr binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural SH2 domains are used, then the structure is simple and easy to manufacture, but the binding affinity to phosphotyrosine-containing proteins is low
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at particular positions within the SH2 domain structure. The modifications are localized to specific regions (such as the BC loop and β-sheet regions) rather than altering the entire domain, thereby enhancing pTyr binding affinity while preserving the overall simple SH2 domain architecture and avoiding excessive complexity
Solution Approach 2:
The patent employs parameter changes by modifying amino acid residues at specific positions within the SH2 domain. These parameter changes (substituting specific amino acids with others that have different properties) alter the binding characteristics of the domain, enabling enhanced affinity for phosphotyrosine-containing proteins while maintaining the fundamental structure
2Reliability
If amino acid substitutions are introduced to enhance pTyr binding, then binding affinity is improved, but the manufacturing complexity increases
Solution Approach 1:
The patent introduces amino acid substitutions at specific localized positions within the SH2 domain (such as positions in the BC loop and β-sheet regions) rather than throughout the entire domain. This localized approach enhances pTyr binding affinity while minimizing the overall complexity of manufacturing, as only specific residues need to be modified
Solution Approach 2:
The patent applies parameter changes by substituting specific amino acid residues with others that have different properties to enhance binding. These targeted parameter changes at specific positions improve pTyr affinity while keeping the manufacturing process relatively simple, as the modifications are limited to specific residues rather than requiring comprehensive domain redesign
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified SH2 domains enhance binding to pTyr-containing proteins, facilitating targeted protein phosphorylation analysis and therapeutic interventions.
Implementation Method 1
the amino acid substitutions provide hydrophobic interactions with pTyr
Implementation Method 2
the Arg residue forms hydrogen bond with pTyr
Data Source
AI summary
The present disclosure provides for high affinity variants of SH2 domains, methods of manufacturing such compositions, their use in screening, and in methods of their administration. The compositions and methods provided herein can be used for targeting protein phosphorylation of tyrosine residues as a means for identifying markers of pathology for therapeutic interventions.