Novel binding mode of the acidic CYP2D6 substrates pactimibe and its metabolite R-125528.

Typical CYP2D6 substrates generally contain a basic nitrogen atom that interacts with Asp(301) and/or Glu(216) and an aromatic moiety adjacent to the site of metabolism. Recently, we found novel acidic substrates for CYP2D6, pactimibe, and its indole metabolite, R-125528, that are not protonated but are negatively charged at physiological pH. The K(m) value of R-125528 in CYP2D6-expressing microsomes was determined to be 1.

Conformational analysis of globomycin with a signal peptidase II inhibitory activity using molecular dynamics simulation.

Globomycin (1), a 19-membered cyclic depsipeptide, exhibited an antibiotic activity against gram-negative bacteria by inhibiting signal peptidase II in the cytoplasmic membrane. Although only one conformation of 1 was observed for the crystal structure, it was revealed by 1H NMR spectroscopic analysis that 1 exists as a mixture of two rotational isomers in solution (CDCl3 and CD3OD). A conformational analysis of 1 was, therefore, performed by high-temperature molecular dynamics simulation in combination with 1H NMR analysis to elucidate the conformations in solution.

An efficient method for reconstructing protein backbones from alpha-carbon coordinates.

We present an approach for building protein backbones from alpha-carbon (Calpha) coordinates. The approach is analytical and based on the information of favored regions in the Ramachandran map. The backbone construction consists of three parts: prediction of (phi, psi) angle pairs from the Calpha trace, generation of atomic coordinates with these (phi, psi) angles, and refinement by subsequent energy minimization.