Stabilized Peptide-MHC Complex via Disulphide Bond Linkage
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Solution Overview
Problem
The instability of isolated peptide-MHC complexes, particularly those involving HLA-E, hampers the development of T cell receptor and antibody-based therapeutics due to rapid dissociation, making it challenging to maintain native-like TCR recognition.
Innovation Solution
Introducing a non-native linkage between the C-terminal anchor residue of the peptide and an amino acid residue in the F pocket of the MHC binding groove, such as a disulphide bond, to stabilize the peptide-MHC complex while retaining its native conformation and recognition by TCRs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If a non-native linkage is introduced between the C-terminal anchor residue and the F pocket residue to stabilize the pMHC complex, then the stability of the complex is improved, but the complexity of the complex structure increases
Solution Approach 1:
The patent applies parameter changes by introducing a non-native linkage (such as a disulphide bond) between the C-terminal anchor residue of the peptide and an amino acid residue in the F pocket of the MHC binding groove. This chemical modification changes the bonding parameters of the complex, transforming it from a weakly bound native complex to a stably bound engineered complex, thereby resolving the stability issue while maintaining recognizability by TCRs
Solution Approach 2:
The non-native linkage acts as an intermediary element that mediates between the peptide and MHC components. This additional chemical bond serves as a bridge that reinforces the interaction without completely altering the native interface, allowing the complex to gain stability while preserving the essential recognition features for TCR binding
2Duration of action of stationary object
If the peptide-MHC complex is stabilized to prevent rapid dissociation, then the duration of complex binding is improved, but the ability to maintain native-like TCR recognition may be compromised
Solution Approach 1:
The patent applies local quality by making a targeted modification only at the C-terminal anchor residue and F pocket region, while leaving the rest of the peptide-MHC interface unchanged. This localized engineering approach allows the complex to gain stability through the non-native linkage while maintaining the native-like conformation and recognition features at the TCR contact sites, thereby resolving the contradiction between stability and recognition reliability
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 stabilized peptide-MHC complexes exhibit significantly improved stability and native-like TCR recognition, with binding half-lives extended by at least 2-5 times, allowing for effective identification and characterization of binding agents.
Implementation Method 1
Introducing a non-native linkage between the C-terminal anchor residue of the peptide and an amino acid residue in the F pocket of the MHC binding groove, such as a disulphide bond, to stabilize the peptide-MHC complex
Data Source
AI summary
The present invention provides a stabilised peptide-MHC (pMHC) complex, such as a peptide-HLA-E complex. The complex has a non-native linkage, such as a disulphide bond, between the C terminal anchor residue of the peptide, and an amino acid residue in the F pocket of the MHC binding groove.