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Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.

Mittal S, Cai Y, Nalam MN, Bolon DN, Schiffer CA
J Am Chem Soc 134 4163-8 (2012)
Related entries: 4dqb, 4dqc, 4dqe, 4dqf, 4dqg

Cited: 39 times
EuropePMC logo PMID: 22295904

Abstract

Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the overall structure of the protease is retained. However, cross-linking the cysteines led to drastic loss in enzyme activity, which was regained upon reducing the disulfide cross-links. Molecular dynamics simulations showed that altered dynamics propagated throughout the enzyme from the engineered disulfide. Thus, altered flexibility within the hydrophobic core can modulate HIV-1 protease activity, supporting the hypothesis that drug resistant mutations distal from the active site can alter the balance between substrate turnover and inhibitor binding by modulating enzyme activity.

Reviews citing this publication (4)

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  13. Four Amino Acid Changes in HIV-2 Protease Confer Class-Wide Sensitivity to Protease Inhibitors. Raugi DN, Smith RA, Gottlieb GS, University of Washington-Dakar HIV-2 Study Group. J Virol 90 1062-1069 (2016)
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  17. Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning. Leidner F, Kurt Yilmaz N, Schiffer CA. J Chem Theory Comput 17 2054-2064 (2021)
  18. I36T↑T mutation in South African subtype C (C-SA) HIV-1 protease significantly alters protease-drug interactions. Maseko SB, Padayachee E, Govender T, Sayed Y, Kruger G, Maguire GEM, Lin J. Biol Chem 398 1109-1117 (2017)
  19. Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation. Chen YS, Gleaton J, Yang Y, Dhayalan B, Phillips NB, Liu Y, Broadwater L, Jarosinski MA, Chatterjee D, Lawrence MC, Hattier T, Michael MD, Weiss MA. Proc Natl Acad Sci U S A 118 e2103518118 (2021)
  20. Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase. Boyer PL, Das K, Arnold E, Hughes SH. Antimicrob Agents Chemother 59 7184-7196 (2015)
  21. Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution. Özer N, Özen A, Schiffer CA, Haliloğlu T. Evol Appl 8 185-198 (2015)
  22. Inhibition of the activity of HIV-1 protease through antibody binding and mutations probed by molecular dynamics simulations. Badaya A, Sasidhar YU. Sci Rep 10 5501 (2020)
  23. Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease. Kumar P, Dominiak PM. Molecules 26 3872 (2021)
  24. Linking function to global and local dynamics in an elevator-type transporter. Ciftci D, Martens C, Ghani VG, Blanchard SC, Politis A, Huysmans GHM, Boudker O. Proc Natl Acad Sci U S A 118 e2025520118 (2021)
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  26. Exploration of the effect of sequence variations located inside the binding pocket of HIV-1 and HIV-2 proteases. Triki D, Billot T, Visseaux B, Descamps D, Flatters D, Camproux AC, Regad L. Sci Rep 8 5789 (2018)
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  28. Acquired HIV-1 Protease Conformational Flexibility Associated with Lopinavir Failure May Shape the Outcome of Darunavir Therapy after Antiretroviral Therapy Switch. Eche S, Kumar A, Sonela N, Gordon ML. Biomolecules 11 489 (2021)
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  31. Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA-approved inhibitors: MD study. Maphumulo SI, Halder AK, Govender T, Maseko S, Maguire GEM, Honarparvar B, Kruger HG. Chem Biol Drug Des 92 1899-1913 (2018)
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