Binding mode of TYY with EphA4 receptor.

<p>(A) 2D interactions between the TYY cyclic peptide and the EphA4 receptor (by LigPlot). Residues with purple bonds in blue labels are from the ligand TYY peptide; residues with brown bonds in red labels are from EphA4. The green dashed line represents a potential hydrogen bond and its length. (B) 3D interactions between the TYY cyclic peptide and the EphA4 receptor (by Pymol). This model was generated by Autodock4, based on the crystal structure of EphA4 in complex with ephrinA2 (PDB: 2WO3). The TYY cyclic peptide is shown as a stick model with grey representing carbon atoms, red representing oxygen atoms and blue representing nitrogen atoms. The EphA4 is shown as a cyan ribbon with key residues shown as yellow sticks. Black dashed lines represent the hydrogen bonds.</p

TYY cyclic peptide inhibits ephrinA5 AP binding to immobilized EphA4 Fc fusion protein.

<p>The KYL peptide was used as a positive control at a concentration of 25 μM. The histogram shows the inhibition of ephrinA5 AP bound to EphA4 in the presence of KYL or TYY at different concentrations. Error bars represent standard errors from three independent measurements.</p

Effects of the TYY cyclic peptide on viability of HUVEC cells.

<p>The HUVECs were treated with the indicated concentrations of the TYY peptide. A 0.1% DMSO control was used because the highest concentration of the DMSO vehicle in the TYY solutions was 0.1%. The cell viability was determined by CellTiter-Blue assays 24 h and 48 h after addition of TYY. Each experimental data point was generated from at least three independent experiments.</p

Superposition of the TYY cyclic peptide with the ephrinA2 G-H loop region from the crystal structure of its complex with the EphA4 receptor (by Pymol, PDB: 2WO3).

<p>The TYY cyclic peptide is shown as a grey stick model, and ephrinA2 G-H loop region is shown as green stick model with red representing oxygen atoms and blue representing nitrogen atoms. The EphA4 is shown as a cyan ribbon. </p

Novel Aromatase Inhibitors by Structure-Guided Design

Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC₅₀ values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC₅₀ values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme–substrate/exemestane complexes. The observed structure–activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs