5 research outputs found
Inhibition of protein interactions: co-crystalized proteinâprotein interfaces are nearly as good as holo proteins in rigid-body ligand docking
Modulating protein interaction pathways may lead to the cure of many diseases. Known proteinâprotein inhibitors bind to large pockets on the proteinâprotein interface. Such large pockets are detected also in the proteinâprotein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation. The conformational change on the protein interface upon binding to the other protein results in a pocket employed by the ligand when it binds to that interface. This proof-of-concept study suggests that rather than using computational pocket-opening procedures, one can opt for an experimentally determined structure of the target co-crystallized proteinâprotein complex as a starting point for drug design
Functional Implications of Structural Predictions for Alternative Splice Proteins Expressed in Her2/neuâInduced Breast Cancers
Alternative splicing allows a single gene to generate multiple mRNA transcripts, which can be translated into functionally diverse proteins. However, experimentally determined structures of protein splice isoforms are rare, and homology modeling methods are poor at predicting atomic-level structural differences because of high sequence identity. Here we exploit the state-of-the-art structure prediction method I-TASSER to analyze the structural and functional consequences of alternative splicing of proteins differentially expressed in a breast cancer model. We first successfully benchmarked the I-TASSER pipeline for structure modeling of all seven pairs of protein splice isoforms, which are known to have experimentally solved structures. We then modeled three cancer-related variant pairs reported to have opposite functions. In each pair, we observed structural differences in regions where the presence or absence of a motif can directly influence the distinctive functions of the variants. Finally, we applied the method to five splice variants overexpressed in mouse Her2/neu mammary tumor: anxa6, calu, cdc42, ptbp1, and tax1bp3. Despite >75% sequence identity between the variants, structural differences were observed in biologically important regions of these protein pairs. These results demonstrate the feasibility of integrating proteomic analysis with structure-based conformational predictions of differentially expressed alternative splice variants in cancers and other conditions
Functional Implications of Structural Predictions for Alternative Splice Proteins Expressed in Her2/neuâInduced Breast Cancers
Inhibition of protein interactions: co-crystalized proteinâprotein interfaces are nearly as good as holo proteins in rigid-body ligand docking
Blind prediction of homo- and hetero-protein complexes: The CASP13-CAPRI experiment
International audienceWe present the results for CAPRI Round 46, the third joint CASPâCAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homoâoligomers and 6 heterocomplexes. Eight of the homoâoligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higherâorder assemblies. These were more difficult to model, as their prediction mainly involved âabâinitioâ docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the nine easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance âgapâ was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in templateâbased modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements