SiteBinder: an improved approach for comparing multiple protein structural motifs.

There is a paramount need to develop new techniques and tools that will extract as much information as possible from the ever growing repository of protein 3D structures. We report here on the development of a software tool for the multiple superimposition of large sets of protein structural motifs. Our superimposition methodology performs a systematic search for the atom pairing that provides the best fit. During this search, the RMSD values for all chemically relevant pairings are calculated by quaternion algebra. The number of evaluated pairings is markedly decreased by using PDB annotations for atoms. This approach guarantees that the best fit will be found and can be applied even when sequence similarity is low or does not exist at all. We have implemented this methodology in the Web application SiteBinder, which is able to process up to thousands of protein structural motifs in a very short time, and which provides an intuitive and user-friendly interface. Our benchmarking analysis has shown the robustness, efficiency, and versatility of our methodology and its implementation by the successful superimposition of 1000 experimentally determined structures for each of 32 eukaryotic linear motifs. We also demonstrate the applicability of SiteBinder using three case studies. We first compared the structures of 61 PA-IIL sugar binding sites containing nine different sugars, and we found that the sugar binding sites of PA-IIL and its mutants have a conserved structure despite their binding different sugars. We then superimposed over 300 zinc finger central motifs and revealed that the molecular structure in the vicinity of the Zn atom is highly conserved. Finally, we superimposed 12 BH3 domains from pro-apoptotic proteins. Our findings come to support the hypothesis that there is a structural basis for the functional segregation of BH3-only proteins into activators and enablers

The Eighth Central European Conference "Chemistry towards Biology": snapshot

The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on 28 August – 1 September 2016The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on 28 August-1 September 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting

Discovery of Molecules that Modulate Protein-Protein Interactions in the Context of Human Proliferating Cell Nuclear Antigen-Associated Processes of DNA Replication and Damage Repair

Integral to cell viability is the homotrimeric protein complex Proliferating Cell Nuclear Antigen (PCNA) that encircles chromatin-bound DNA and functionally acts as a DNA clamp that provides topological sites for recruitment of proteins necessary for DNA replication and damage repair. PCNA has critical roles in the survival and proliferation of cells, as disease-associated dysregulation of associated functions can have dire effects on genome stability, leading to the formation of various malignancies ranging from non-Hodgkin’s lymphoma to skin, laryngeal, ocular, prostate and breast cancers. Here, a strategy was explored with PCNA as a drug target that may have wider implications for targeting protein-protein interactions (PPIs) as well as for fragment-based drug design. A design platform using peptidomimetic small molecules was developed that maps ideal surface binding interaction sites at a PPI interface before considering detailed conformations of an optimal ligand. A novel in silico multi-fragment, combinatorial screening approach was used to guide the selection and subsequent synthesis of tripeptoid ligands, which were evaluated in a PCNA-based competitive displacement assay. From the results, some of the peptoid-based compounds that were synthesized displayed the ability to disrupt the interaction between PCNA and a PIP box-containing peptide. The IC50 values of these compounds had similar or improved affinity to that of T2AA, an established inhibitor of PCNA-PIP box interactions. The information gained here could be useful for subsequent drug lead candidate identification