Structural effects of protease mutations and inhibitor modifications
Years: 1998-2006
PDB codes: 1ZSF, 1ZSR, 1ZJ7, 1ZLF, 1M0B, 1LZQ, 1IIQ, 1FQX, 1ZBG, 1ZPK
The project was aimed to structure analysis of series of complexes of HIV-1 protease (wild type and two mutant forms as explained in Fig. 1) with similar peptidomimetic inhibitors differing in two positions as explained in Fig. 1:
a) Peptide bond isostere (hydroxyethylamine isostere with OH in configuration R or S (denoted as R or S) or ethyleneamine isostere (denoted as O))
b) Amino acid residue in P2' position (glutamic acid: E, glutamine acid: Q, isoleucine: I)
These two variant positions gave denotation of the inhibitors: RE, SE, OE and SQ.
Fig. 1. Explanation of nomenclature used in this series of HIV-1 protease-inhibitor complexes.
Fig. 2. Summary of X-ray structures of HIV-1 protease-inhibitor complexes solved in this project. Listed details: column - protease mutant, row - inhibitor type, cells: PDB code, space group and resolution.
Complexes of HIV-1 protease with inhibitors were thoroughly analyzed both by methods of X-ray crystallography and molecular modeling. Shortly, we found that:
a) All complexes studied have rich net of hydrogen bonds between protease and inhibitor. Van der Waals interaction is dominant component of protease-inhibitor interaction energy.
b) Protease mutants: Protease-inhibitor interaction energy changes caused by mutations V82T and I84V are mainly changes in van der Waals energy. Mutation A71V is far from the active site, but it is possible to trace several hydrogen bonds along which it is possible to transfer structural change A71V from the mutation place to the inhibitor.
c) Conformational strain of the inhibitors bound in the protease seems to be the best correlating term when looking for easy relationship between inhibition constant and protease-inhibitor complex.
d) Differences between X-ray structures of protease-inhibitor complexes: we observed mainly high variability of positions of phenylalanine residue in P1 position.