A Phenylnorstatine Inhibitor Binding to HIV-1 Protease: Geometry, Protonation and Subsite-Pocket Interactions Analyzed at Atomic Resolution

Jiri Brynda,* Pavlina Rezacova, Milan Fabry, Magdalena Horejsi, Renata Stouracova, and Juraj Sedlacek

Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16637 Prague6

Milan Soucek, Martin Hradilek, Martin Lepsik, and Jan Konvalinka

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 16610 Prague 6


The x-ray structure of a complex of HIV-1 protease (PR) with a phenylnorstatine inhibitor Z‑Pns‑Phe‑Glu‑Glu‑NH2 has been determined at 1.03 Å, the highest resolution so far reported for any HIV PR complex. The inhibitor shows subnanomolar Ki values for both the wild‑type PR and the variant representing one of the most common mutations linked to resistance development. The structure displays a unique pattern of hydrogen bonding to the two catalytic aspartate residues. The high resolution permits to assess the donor/acceptor relations of this hydrogen bonding, and to indicate a proton shared by the two catalytic residues. Structural mechanism for the unimpaired inhibition of the protease Val82Ala mutant is also suggested, based on energy calculations and analyses.