Resistance mechanism revealed by crystal structures of unliganded nelfinavir-resistant HIV-1 protease non-active site mutants N88D and N88S.
Nelfinavir is an inhibitor of HIV-1 protease, and is used for treatment of patients suffering from HIV/AIDS. However, treatment results in drug resistant mutations in HIV-1 protease. N88D and N88S are two such mutations which occur in the non-active site region of the enzyme. We have determined crystal structures of unliganded N88D and N88S mutants of HIV-1 protease to resolution of 1.65A and 1.8A, respectively. These structures refined against synchrotron data lead to R-factors of 0.1859 and 0.1780, respectively. While structural effects of N88D are very subtle, the mutation N88S has caused a significant conformational change in D30, an active site residue crucial for substrate and inhibitor binding.
Bihani
Subhash C
SC
Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
Das
Amit
A
Prashar
Vishal
V
Ferrer
J-L
JL
Hosur
M V
MV
D001216:Asparagine / Q000737:chemistry / Q000235:genetics; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics; D002219:Carbamates / Q000494:pharmacology; D020134:Catalytic Domain / Q000235:genetics; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics*; D005663:Furans; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D001224:Aspartic Acid; C095108:amprenavir; D001216:Asparagine; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019888:Nelfinavir