The human pituitary tumor-transforming gene-1 (hPTTG1) has been found to be overexpressed in various cancers. Accumulated evidences implicate that some of protein kinases can specifically recognize two PXXP motifs at hPTTG1 C-terminus through their Src homology (SH3) domain and then phosphorylate the protein by their catalytic domain. Here, we integrate in silico analysis and in vitro assay to characterize the intermolecular interaction between the two hPTTG1 motif peptides 161LGPPSPVK168 (M1P) and 168KMPSPPWE175 (M2P) and the SH3 domains of Ser/Thr-specific protein kinases MAP3K and PI3K. It is identified that the two peptides bind to MAP3K SH3 domain with a moderate affinity, but cannot form stable complexes with PI3K SH3 domain. Long time scale molecular dynamics (MD) simulations reveal that the M1P peptide can fold into a standard poly-proline II helix that is bound in the peptide-binding pocket of MAP3K SH3 domain, while the M2P peptide gradually moves out of the pocket during the simulations and finally forms a weak, transient encounter complex with the domain. All these suggest that the MAP3K M1P site is a potential interacting partner of MAP3K SH3 domain, which may mediate the intermolecular recognition between hPTTG1 and MAP3K.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.4149/gpb_2016035 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of anti-tumor small molecule lead compounds targeting the SH3 domain of c-Src protein through virtual screening and biological evaluation.
Arch Biochem Biophys
December 2024
Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address:
c-Src, also known as cellular Src, is a non-receptor tyrosine kinase that plays a crucial role in various cellular processes, including cell proliferation, adhesion, and migration. Its dysregulation has been implicated in the development and progression of several diseases, particularly cancer. Current therapeutic agents targeting c-Src are primarily small molecules binding to its kinase domain.
View Article and Find Full Text PDFThe structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain.
Protein Sci
January 2025
Department of Physics, University of Toronto, Toronto, Ontario, Canada.
The point mutation N642H of the signal transducer and activator of transcription 5B (STAT5B) protein is associated with aggressive and drug-resistant forms of leukemia. This mutation is thought to promote cancer due to hyperactivation of STAT5B caused by increased stability of the active, parallel dimer state. However, the molecular mechanism leading to this stabilization is not well understood as there is currently no structure of the parallel dimer.
View Article and Find Full Text PDFAllosteric regulation of the tyrosine phosphatase PTP1B by a protein-protein interaction.
Protein Sci
January 2025
Department of Chemistry, Columbia University, New York, New York, USA.
The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter protein function or cell signaling. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized.
View Article and Find Full Text PDFDevelopment of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase.
Nat Commun
December 2024
Institute of Physiological Chemistry, Faculty of Medicine, Philipps University of Marburg, Marburg, Germany.
Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D-binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L-)binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis.
View Article and Find Full Text PDFDisruption of Molecular Interactions between the G3BP1 Stress Granule Host Protein and the Nucleocapsid (NTD-N) Protein Impedes SARS-CoV-2 Virus Replication.
Biochemistry
December 2024
Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
The Ras GTPase-activating protein SH3-domain-binding protein 1 (G3BP1) serves as a formidable barrier to viral replication by generating stress granules (SGs) in response to viral infections. Interestingly, viruses, including SARS-CoV-2, have evolved defensive mechanisms to hijack SG proteins like G3BP1 for the dissipation of SGs that lead to the evasion of the host's immune responses. Previous research has demonstrated that the interaction between the NTF2-like domain of G3BP1 (G3BP1) and the intrinsically disordered N-terminal domain (NTD-N) of the N-protein plays a crucial role in regulating viral replication and pathogenicity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!