Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation

Fengling Liu; Andrey Y. Kovalevsky; John M. Louis; Peter I. Boross; Yuan Fang Wang; Robert W. Harrison; Irene T. Weber

doi:10.1016/j.jmb.2006.02.076

Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation

Fengling Liu, Andrey Y. Kovalevsky, John M. Louis, Peter I. Boross, Yuan Fang Wang, Robert W. Harrison, Irene T. Weber

Research output: Contribution to journal › Article › peer-review

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Abstract

Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PR_F53L showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PR_F53L was determined in the unliganded form at 1.35 Å resolution in space group P4₁2₁2. The tips of the flaps in PR_F53L had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50′. The changes in interactions between the flaps agreed with the reduced stability of PR_F53L relative to wild-type PR. The altered flap interactions in the unliganded form of PR_F53L suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants.

Original language	English
Pages (from-to)	1191-1199
Number of pages	9
Journal	Journal of Molecular Biology
Volume	358
Issue number	5
DOIs	https://doi.org/10.1016/j.jmb.2006.02.076
State	Published - May 19 2006
Externally published	Yes

Funding

We thank Yunfeng Tie and Ping Liu for assistance with X-ray data collection. The X-ray diffraction data were recorded at SER-CAT ID-22 beamline of the Advanced Photon Source at Argonne National Laboratory, which is supported by the U.S. Department of Energy, Basic Energy Sciences and Office of Science, under Contract No. W-31-109-Eng-38. The research was supported, in part, by the Georgia Research Alliance, the Georgia Cancer Coalition, National Institute of Health grants GM062920, AIDS-FIRCA TW01001, Hungarian OTKA F35191 and the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases, NIH.

Funders	Funder number
National Institutes of Health	AIDS-FIRCA TW01001
U.S. Department of Energy
National Institute of General Medical Sciences	R01GM062920
National Institute of Diabetes and Digestive and Kidney Diseases
Georgia Cancer Coalition
Office of Science	W-31-109-Eng-38
Basic Energy Sciences
Georgia Research Alliance
Hungarian Scientific Research Fund	F35191

Keywords

aspartic protease
catalysis
flap mutant
non-active site mutant
unliganded

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jmb.2006.02.076

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title = "Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation",

abstract = "Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PRF53L showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PRF53L was determined in the unliganded form at 1.35 {\AA} resolution in space group P41212. The tips of the flaps in PRF53L had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50′. The changes in interactions between the flaps agreed with the reduced stability of PRF53L relative to wild-type PR. The altered flap interactions in the unliganded form of PRF53L suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants.",

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AU - Wang, Yuan Fang

AU - Harrison, Robert W.

AU - Weber, Irene T.

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AB - Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PRF53L showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PRF53L was determined in the unliganded form at 1.35 Å resolution in space group P41212. The tips of the flaps in PRF53L had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50′. The changes in interactions between the flaps agreed with the reduced stability of PRF53L relative to wild-type PR. The altered flap interactions in the unliganded form of PRF53L suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants.

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Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation

Abstract

Funding

Keywords

UN SDGs

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