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Effects of Hinge-region Natural Polymorphisms on Human Immunodeficiency Virus-Type 1 Protease Structure, Dynamics, and Drug Pressure Evolution.

Liu Z, Huang X, Hu L, Pham L, Poole KM, Tang Y, Mahon BP, Tang W, Li K, Goldfarb NE, Dunn BM, McKenna R, Fanucci GE
J Biol Chem 291 22741-22756 (2016)
Related entries: 5kqx, 5kqz, 5kr0, 5kr1, 5kr2

Cited: 12 times
EuropePMC logo PMID: 27576689

Abstract

Multidrug resistance to current Food and Drug Administration-approved HIV-1 protease (PR) inhibitors drives the need to understand the fundamental mechanisms of how drug pressure-selected mutations, which are oftentimes natural polymorphisms, elicit their effect on enzyme function and resistance. Here, the impacts of the hinge-region natural polymorphism at residue 35, glutamate to aspartate (E35D), alone and in conjunction with residue 57, arginine to lysine (R57K), are characterized with the goal of understanding how altered salt bridge interactions between the hinge and flap regions are associated with changes in structure, motional dynamics, conformational sampling, kinetic parameters, and inhibitor affinity. The combined results reveal that the single E35D substitution leads to diminished salt bridge interactions between residues 35 and 57 and gives rise to the stabilization of open-like conformational states with overall increased backbone dynamics. In HIV-1 PR constructs where sites 35 and 57 are both mutated (e.g. E35D and R57K), x-ray structures reveal an altered network of interactions that replace the salt bridge thus stabilizing the structural integrity between the flap and hinge regions. Despite the altered conformational sampling and dynamics when the salt bridge is disrupted, enzyme kinetic parameters and inhibition constants are similar to those obtained for subtype B PR. Results demonstrate that these hinge-region natural polymorphisms, which may arise as drug pressure secondary mutations, alter protein dynamics and the conformational landscape, which are important thermodynamic parameters to consider for development of inhibitors that target for non-subtype B PR.

Articles - 5kqy mentioned but not cited (1)

  1. Effects of Hinge-region Natural Polymorphisms on Human Immunodeficiency Virus-Type 1 Protease Structure, Dynamics, and Drug Pressure Evolution. Liu Z, Huang X, Hu L, Pham L, Poole KM, Tang Y, Mahon BP, Tang W, Li K, Goldfarb NE, Dunn BM, McKenna R, Fanucci GE. J Biol Chem 291 22741-22756 (2016)


Articles citing this publication (11)

  1. Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics. Sheik Amamuddy O, Bishop NT, Tastan Bishop Ö. Sci Rep 8 17938 (2018)
  2. HIV-1 protease and reverse transcriptase inhibition by tiger milk mushroom (Lignosus rhinocerus) sclerotium extracts: In vitro and in silico studies. Sillapachaiyaporn C, Chuchawankul S. J Tradit Complement Med 10 396-404 (2020)
  3. HIV-1 Protease and Reverse Transcriptase Inhibitory Activities of Curcuma aeruginosa Roxb. Rhizome Extracts and the Phytochemical Profile Analysis: In Vitro and In Silico Screening. Sillapachaiyaporn C, Rangsinth P, Nilkhet S, Moungkote N, Chuchawankul S. Pharmaceuticals (Basel) 14 1115 (2021)
  4. Highly drug-resistant HIV-1 protease reveals decreased intra-subunit interactions due to clusters of mutations. Kneller DW, Agniswamy J, Harrison RW, Weber IT. FEBS J 287 3235-3254 (2020)
  5. Darunavir-Resistant HIV-1 Protease Constructs Uphold a Conformational Selection Hypothesis for Drug Resistance. Liu Z, Tran TT, Pham L, Hu L, Bentz K, Savin DA, Fanucci GE. Viruses 12 E1275 (2020)
  6. Predicting robotic-assisted total knee arthroplasty operating time : benefits of machine-learning and 3D patient-specific data. Motesharei A, Batailler C, De Massari D, Vincent G, Chen AF, Lustig S. Bone Jt Open 3 383-389 (2022)
  7. Energetics of Flap Opening in HIV-1 Protease: String Method Calculations. Gardner JM, Abrams CF. J Phys Chem B 123 9584-9591 (2019)
  8. Crystal structures of inhibitor complexes of M-PMV protease with visible flap loops. Wosicki S, Kazmierczyk M, Gilski M, Zabranska H, Pichova I, Jaskolski M. Protein Sci 30 1258-1263 (2021)
  9. Beyond structure: Deciphering site-specific dynamics in proteins from double histidine-based EPR measurements. Singewald K, Wilkinson JA, Hasanbasri Z, Saxena S. Protein Sci 31 e4359 (2022)
  10. HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics. Wong-Sam A, Wang YF, Kneller DW, Kovalevsky AY, Ghosh AK, Harrison RW, Weber IT. J Mol Graph Model 117 108315 (2022)
  11. Role of diosgenin extracted from Helicteres isora L in suppression of HIV-1 replication: An in vitro preclinical study. Rakshit S, More A, Gaikwad S, Seniya C, Gade A, Muley VY, Mukherjee A, Kamble K. Heliyon 10 e24350 (2024)


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