Structure of the adenylation domain of NAD+-dependent DNA ligase from Staphylococcus aureus

The crystal structure of the adenylation domain of NAD+-dependent DNA ligase from Staphylococcus aureus reveals a narrow ‘C2 tunnel’ for potential use in inhibitor design

Crystal structure of activin receptor type IIB kinase domain from human at 2.0 Å resolution

Activin receptor type IIB (ActRIIB), a type II TGF-β serine/threonine kinase receptor, is integral to the activin and myostatin signaling pathway. Ligands such as activin and myostatin bind to activin type II receptors (ActRIIA, ActRIIB), and the GS domains of type I receptors are phosphorylated by type II receptors. Myostatin, a negative regulator of skeletal muscle growth, is regarded as a potential therapeutic target and binds to ActRIIB effectively, and to a lesser extent, to ActRIIA. The high-resolution structure of human ActRIIB kinase domain in complex with adenine establishes the conserved bilobal architecture consistent with all other catalytic kinase domains. The crystal structure reveals that the adenine has a considerably different orientation from that of the adenine moiety of ATP observed in other kinase structures due to the lack of an interaction by ribose-phosphate moiety and the presence of tautomers with two different protonation states at the N9 nitrogen. Although the Lys217–Glu230 salt bridge is absent, the unphosphorylated activation loop of ActRIIB adopts a conformation similar to that of the fully active form. Unlike the type I TGF-β receptor, where a partially conserved Ser280 is a gatekeeper residue, the AcRIIB structure possesses Thr265 with a back pocket supported by Phe247. Taken together, these structural features provide a molecular basis for understanding the coupled activity and recognition specificity for human ActRIIB kinase domain and for the rational design of selective inhibitors

Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro

Disrupting the binding interaction between proprotein convertase (PCSK9) and the epidermal growth factor-like domain A (EGF-A domain) in the low-density lipoprotein receptor (LDL-R) is a promising strategy to promote LDL-R recycling and thereby lower circulating cholesterol levels. In this study, truncated 26 amino acid EGF-A analogs were designed and synthesized, and their structures were analyzed in solution and in complex with PCSK9. The most potent peptide had an increased binding affinity for PCSK9 (K-D = 0.6 mu M) compared with wild-type EGF-A (K-D = 1.2 mu M), and the ability to increase LDL-R recycling in the presence of PCSK9 in a cell-based assay