Peptide Inhibitors of Protein-Protein Interactions Targeted to Src Homology 2 Domains: A Combined Computational and Spectroscopic Design Approach
Year: 2024
Type: conference-abstract
Abstract: SHP2 is an important molecular target for therapies against cancer and rare diseases, like RASopathies [1,2].Mutations of the gene coding for SHP2, PTPN11, have been associated with cancer and developmental disorders.The structure of SHP2 includes two SH2 domains (N-SH2 and C-SH2) followed by the catalytic domain PTP.SH2 domains recognize and bind phosphopeptide [3].They also have an important role in modulating the catalytic activity of the protein.Under basal conditions, the N-SH2 domain blocks the catalytic site and SHP2 is inactive.The association to binding partners favors a conformational transition from this autoinhibited conformation to an active state.Most of the SHP2 pathological amino acid substitutions perturb the autoinhibitory interaction in favor of open conformations, resulting in a hyperactivated protein [4].SHP2 can be efficiently inhibited by targeting the binding of the N-SH2 domain to cognate proteins [5], furthermore the development of inhibitors of SHP2 protein-protein interactions can take advantage of the role of the C-SH2 domain for increasing both specificity and affinity.Further developments REFERENCES Minimal high affinity sequence length Affinity improvement CF-GLN-pY-IDLDW 𝐾 !=(5.3±0.6)Nm CF-GLN-pY-IDVDW 𝐾 !=(15.3±0.2) nM CF-GLN-pY-IELDW 𝐾 !=(1.66±0.03)nM
Source: European Peptide Symposium (EPS)
Authors: Paolo Calligari, Claudia Storti, Chiara Innamorati, Chiara Fulci, Alessia Damiani, Cristiano DI Stefano, Chiara Cocca, Cristina Peggion, Barbara Biondi, Gianfranco Bocchinfuso, Lorenzo Stella
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4403191569