Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Drug resistance: Crystallography of drug-resistant HIV-1 protease mutant
HIV-1 protease is an attractive target for developing drugs against AIDS, since a functional protease is required for production of mature and infectious AIDS virus. A number of crystal structures have been determined to help in this process (Prabu-Jeyabalan et al., 2002; Prashar et al.,2010; Das et al., 2010; Das et al. 2006). However, mutations that confer resistance quickly emerge and make a given drug ineffective. V82S is one of the active-site mutations, which occurs when the HIV infected patient is treated with anti-AIDS drugs, ritonavir, nelfinavir and indinavir. This mutation confers approximately 15-30 fold resistance against these inhibitors. It has also been reported that the catalytic activity of V82S mutant is reduced to 2-20% of the wild-type HIV-1 Protease. In order to understand these phenomena at an atomic level, we have undertaken to solve crystal structures of unliganded and ligand complexed HIV-1 protease. Here we report the crystal structure of unliganded V82S mutant of HIV-1 protease. The structure has been refined against diffraction data to 2.4 Å resolution collected using the ACTREC X-ray diffraction Facility. The crystallographic R-factors at the end of refinement are: Rwork = 19.5%, Rfree= 25.6%, and the model stereochemistry is excellent. The S82/S1082 conformations in the present unliganded structure are stabilized by multiple weak hydrogen bonds. The catalytic water molecule in the present structure is shifted significantly compared to its position in the wild-type enzyme. When the mutant structure is compared with structures of wild-type enzyme complexed with substrates/inhibitors, it is found that the residues S82/S1082 would either form too short steric contacts or are too far for van der Waals interactions with P1/P1'moieties. The multiple weak hydrogen bonds stabilizing S82/S1082 rotamers in the present structure need to be broken to change the rotamers, and this, we suggest, contributes to the drug-resistance and reduced catalytic power of V82S mutant HIV-1 protease.