Dataset Information

Meditope-Fab interaction: threading the hole.

ABSTRACT: Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.

SUBMITTER: Bzymek KP

PROVIDER: S-EPMC5713674 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Meditope-Fab interaction: threading the hole.

Bzymek Krzysztof P KP Ma Yuelong Y Avery Kendra N KN Horne David A DA Williams John C JC

Acta crystallographica. Section F, Structural biology communications 20171118 Pt 12

Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The ato ...[more]

PMID: 29199990

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Project description:Amyloid proteins are often associated with the onset of diseases, including Alzheimer's, Parkinson's and many others. However, there is a wide class of functional amyloids that are involved in physiological functions, e.g., formation of microbial biofilms or storage of hormones. Recent studies showed that an amyloid fibril could affect the aggregation of another protein, even from a different species. This may result in amplification or attenuation of the aggregation process. Insight into amyloid cross-interactions may be crucial for better understanding of amyloid diseases and the potential influence of microbial amyloids on human proteins. However, due to the demanding nature of the needed experiments, knowledge of such interactions is still limited. Here, we present PACT (Prediction of Amyloid Cross-interaction by Threading) - the computational method for the prediction of amyloid cross-interactions. The method is based on modeling of a heterogeneous fibril formed by two amyloidogenic peptides. The resulting structure is assessed by the structural statistical potential that approximates its plausibility and energetic stability. PACT was developed and first evaluated mostly on data collected in the AmyloGraph database of interacting amyloids and achieved high values of Area Under ROC (AUC=0.88) and F1 (0.82). Then, we applied our method to study the interactions of CsgA - a bacterial biofilm protein that was not used in our in-reference datasets, which is expressed in several bacterial species that inhabit the human intestines - with two human proteins. The study included alpha-synuclein, a human protein that is involved in Parkinson's disease, and human islet amyloid polypeptide (hIAPP), which is involved in type 2 diabetes. In both cases, PACT predicted the appearance of cross-interactions. Importantly, the method indicated specific regions of the proteins, which were shown to play a central role in both interactions. We experimentally confirmed the novel results of the indicated CsgA fragments interacting with hIAPP based on the kinetic characteristics obtained with the ThT assay. PACT opens the possibility of high-throughput studies of amyloid interactions. Importantly, it can work with fairly long protein fragments, and as a purely physicochemical approach, it relies very little on scarce training data. The tool is available as a web server at https://pact.e-science.pl/pact/ . The local version can be downloaded from https://github.com/KubaWojciechowski/PACT .

Dataset Information

Meditope-Fab interaction: threading the hole.

Publications

Meditope-Fab interaction: threading the hole.

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