Molecular Dynamics Studies of the STAT3 Homodimer:DNA Complex: Relationships between STAT3 Mutations and Protein–DNA Recognition

Signal Transducers and Activators of Transcription (STAT) proteins are a group of latent cytoplasmic transcription factors involved in cytokine signaling. STAT3 is a member of the STAT family and is expressed at elevated levels in a large number of diverse human cancers and is now a validated target for anticancer drug discovery.. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein–DNA and protein–protein interactions, with respect to the dynamics of the latent unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. Molecular dynamics (MD) simulations have been used to study the activated STAT3 homodimer:DNA complex and the latent unphosphorylated STAT3 monomer in an explicit water environment. Analysis of the data obtained from MD simulations over a 50 ns time frame has suggested how the transcription factor interacts with DNA, the nature of the conformational changes, and ways in which function may be affected. Examination of the dimer interface, focusing on the protein–DNA interactions, including involvement of water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein–DNA interactions. This has shown that the majority of mutations in the DNA-binding domain are found at the protein–DNA interface. These mutations have been mapped in detail and related to specific protein–DNA contacts. Their structural stability is described, together with an analysis of the model as a starting-point for the discovery of novel small-molecule STAT3 inhibitors

Molecular Basis of Structure–Activity Relationships between Salphen Metal Complexes and Human Telomeric DNA Quadruplexes

The first X-ray crystal structures of nickel­(II) and copper­(II) salphen metal complexes bound to a quadruplex DNA are presented. Two structures have been determined and show that these salphen–metal complexes bind to human telomeric quadruplexes by end-stacking, with the metal in each case almost in line with the potassium ion channel. Quadruplex and duplex DNA binding is presented for these two and other related salphen complexes, all with side-chains terminating in pyrrolidino end-groups and differing patterns of substitution on the salphen core. The crystal structures are able to provide rationalizations for the structure–activity data, and in particular for the superior quadruplex-binding of the nickel complexes compared to that of the copper-containing ones. The complexes show significant antiproliferative activity for the compounds in a panel of cancer cell lines. They also show telomerase inhibitory activity in the telomerase TRAP-LIG assay