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Resistance mechanism revealed by crystal structures of unliganded nelfinavir-resistant HIV-1 protease non-active site mutants N88D and N88S.

Bihani SC, Das A, Prashar V, Ferrer JL, Hosur MV
Biochem Biophys Res Commun 389 295-300 (2009)
Cited: 7 times
EuropePMC logo PMID: 19720046

Abstract

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.

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  1. [Bioinformatics studies on drug resistance against anti-HIV-1 drugs]. Ode H. Uirusu 61 35-47 (2011)

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  1. Extreme multidrug resistant HIV-1 protease with 20 mutations is resistant to novel protease inhibitors with P1'-pyrrolidinone or P2-tris-tetrahydrofuran. Agniswamy J, Shen CH, Wang YF, Ghosh AK, Rao KV, Xu CX, Sayer JM, Louis JM, Weber IT. J Med Chem 56 4017-4027 (2013)
  2. Small molecule regulation of protein conformation by binding in the Flap of HIV protease. Tiefenbrunn T, Forli S, Baksh MM, Chang MW, Happer M, Lin YC, Perryman AL, Rhee JK, Torbett BE, Olson AJ, Elder JH, Finn MG, Stout CD. ACS Chem Biol 8 1223-1231 (2013)
  3. Flexible catalytic site conformations implicated in modulation of HIV-1 protease autoprocessing reactions. Huang L, Li Y, Chen C. Retrovirology 8 79 (2011)
  4. Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring. Chang YC, Yu X, Zhang Y, Tie Y, Wang YF, Yashchuk S, Ghosh AK, Harrison RW, Weber IT. J Med Chem 55 3387-3397 (2012)
  5. Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Bastys T, Gapsys V, Walter H, Heger E, Doncheva NT, Kaiser R, de Groot BL, Kalinina OV. Retrovirology 17 13 (2020)


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