Mutant HLA-E Heavy Chain Crosslinking for Peptide Stability
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Solution Overview
Problem
The existing methods for stabilizing HLA-E:peptide complexes are inadequate, as they often result in conformational changes to the natural complex, limiting the identification and validation of peptides that bind to HLA-E, especially for therapeutic applications in cancer and infections, due to the weak binding affinity of many peptides.
Innovation Solution
A mutant HLA-E heavy chain with specific mutations, such as cysteine introduction at positions 84 and 139, allows for crosslinking with peptides via disulphide bonds, enhancing the stability of the HLA-E:peptide complex while maintaining the natural conformation, thereby increasing the binding affinity of low-affinity peptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If existing stabilization methods are used to strengthen HLA-E:peptide complex interaction, then binding strength is improved, but conformational changes occur to the natural complex
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the HLA-E molecule (positions 84, 139, and 147) to cysteine, tryptophan, or tyrosine respectively. These parameter changes in the molecular structure enable covalent crosslinking with peptides while preserving the natural conformation of the HLA-E:peptide complex, resolving the contradiction between strengthening binding and maintaining shape.
2Quantity of substance
If many low-affinity peptides are tested, then the number of potential epitope peptides increases, but the complexity of identification and validation increases
Solution Approach 1:
The patent uses covalent crosslinking as an intermediary mechanism to stabilize low-affinity peptide:HLA-E complexes. This intermediary approach allows weak binders to be captured and stabilized for subsequent identification and validation, increasing the number of detectable epitope peptides without proportionally increasing the complexity of the identification process.
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 mutant HLA-E:peptide complexes demonstrate increased thermal stability and antigenicity, enabling reliable identification of therapeutic antibodies and T-cell receptors that recognize the complex, facilitating the development of specific monoclonal antibodies and chimeric receptors for cancer and infection treatments.
Implementation Method 1
allows for crosslinking with peptides via disulphide bonds
Data Source
AI summary
The invention relates to a mutant HLA-E heavy chain comprising one or more mutation which permits the formation of a HLA-E:peptide complex with increased stability when compared to the complex without the mutant HLA-E heavy chain. The invention also relates to a peptide which is capable of being crosslinked to the mutant HLA-E heavy chain, and a protein complex comprising or consisting of the mutant HLA-E heavy chain and peptide.