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Solution structure of the mature HIV-1 protease monomer: insight into the tertiary fold and stability of a precursor.

Ishima R, Torchia DA, Lynch SM, Gronenborn AM, Louis JM
J Biol Chem 278 43311-9 (2003)
Cited: 54 times
EuropePMC logo PMID: 12933791

Abstract

We present the first solution structure of the HIV-1 protease monomer spanning the region Phe1-Ala95 (PR1-95). Except for the terminal regions (residues 1-10 and 91-95) that are disordered, the tertiary fold of the remainder of the protease is essentially identical to that of the individual subunit of the dimer. In the monomer, the side chains of buried residues stabilizing the active site interface in the dimer, such as Asp25, Asp29, and Arg87, are now exposed to solvent. The flap dynamics in the monomer are similar to that of the free protease dimer. We also show that the protease domain of an optimized precursor flanked by 56 amino acids of the N-terminal transframe region is predominantly monomeric, exhibiting a tertiary fold that is quite similar to that of PR1-95 structure. This explains the very low catalytic activity observed for the protease prior to its maturation at its N terminus as compared with the mature protease, which is an active stable dimer under identical conditions. Adding as few as 2 amino acids to the N terminus of the mature protease significantly increases its dissociation into monomers. Knowledge of the protease monomer structure and critical features of its dimerization may aid in the screening and design of compounds that target the protease prior to its maturation from the Gag-Pol precursor.

Reviews - 1q9p mentioned but not cited (1)

  1. Constraint methods that accelerate free-energy simulations of biomolecules. Perez A, MacCallum JL, Coutsias EA, Dill KA. J Chem Phys 143 243143 (2015)

Articles - 1q9p mentioned but not cited (4)

  1. Assessing protein loop flexibility by hierarchical Monte Carlo sampling. Nilmeier J, Hua L, Coutsias EA, Jacobson MP. J Chem Theory Comput 7 1564-1574 (2011)
  2. Visualization of early events in acetic acid denaturation of HIV-1 protease: a molecular dynamics study. Borkar AN, Borkar AN, Rout MK, Hosur RV. PLoS One 6 e19830 (2011)
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  4. Kinematic Reconstruction of Cyclic Peptides and Protein Backbones from Partial Data. Hassan M, Coutsias EA. J Chem Inf Model 61 4975-5000 (2021)


Reviews citing this publication (2)

  1. Protein intrinsic disorder as a flexible armor and a weapon of HIV-1. Xue B, Mizianty MJ, Kurgan L, Uversky VN. Cell Mol Life Sci 69 1211-1259 (2012)
  2. Foamy virus assembly with emphasis on pol encapsidation. Lee EG, Stenbak CR, Linial ML. Viruses 5 886-900 (2013)

Articles citing this publication (47)

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  4. Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease. Sayer JM, Liu F, Ishima R, Weber IT, Louis JM. J Biol Chem 283 13459-13470 (2008)
  5. Importance of protease cleavage sites within and flanking human immunodeficiency virus type 1 transframe protein p6* for spatiotemporal regulation of protease activation. Ludwig C, Leiherer A, Wagner R. J Virol 82 4573-4584 (2008)
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  7. Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir. Hayashi H, Takamune N, Nirasawa T, Aoki M, Morishita Y, Das D, Koh Y, Ghosh AK, Misumi S, Mitsuya H. Proc Natl Acad Sci U S A 111 12234-12239 (2014)
  8. Loss of protease dimerization inhibition activity of darunavir is associated with the acquisition of resistance to darunavir by HIV-1. Koh Y, Aoki M, Danish ML, Aoki-Ogata H, Amano M, Das D, Shafer RW, Ghosh AK, Mitsuya H. J Virol 85 10079-10089 (2011)
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  15. A folding inhibitor of the HIV-1 protease. Broglia RA, Provasi D, Vasile F, Ottolina G, Longhi R, Tiana G. Proteins 62 928-933 (2006)
  16. Evidence that the Bacillus subtilis SpoIIGA protein is a novel type of signal-transducing aspartic protease. Imamura D, Zhou R, Feig M, Kroos L. J Biol Chem 283 15287-15299 (2008)
  17. Revealing the dimer dissociation and existence of a folded monomer of the mature HIV-2 protease. Louis JM, Ishima R, Aniana A, Sayer JM. Protein Sci 18 2442-2453 (2009)
  18. Targeting the open-flap conformation of HIV-1 protease with pyrrolidine-based inhibitors. Böttcher J, Blum A, Dörr S, Heine A, Diederich WE, Klebe G. ChemMedChem 3 1337-1344 (2008)
  19. Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme. Park JH, Sayer JM, Aniana A, Yu X, Weber IT, Harrison RW, Louis JM. Biochemistry 55 2390-2400 (2016)
  20. Disruption of the HIV-1 protease dimer with interface peptides: structural studies using NMR spectroscopy combined with [2-(13)C]-Trp selective labeling. Frutos S, Rodriguez-Mias RA, Madurga S, Collinet B, Reboud-Ravaux M, Ludevid D, Giralt E. Biopolymers 88 164-173 (2007)
  21. Highly conserved glycine 86 and arginine 87 residues contribute differently to the structure and activity of the mature HIV-1 protease. Ishima R, Gong Q, Tie Y, Weber IT, Louis JM. Proteins 78 1015-1025 (2010)
  22. Foamy retrovirus integrase contains a Pol dimerization domain required for protease activation. Lee EG, Roy J, Jackson D, Clark P, Boyer PL, Hughes SH, Linial ML. J Virol 85 1655-1661 (2011)
  23. Modulation of human immunodeficiency virus type 1 protease autoprocessing by charge properties of surface residue 69. Huang L, Sayer JM, Swinford M, Louis JM, Chen C. J Virol 83 7789-7793 (2009)
  24. Role of Conformational Motions in Enzyme Function: Selected Methodologies and Case Studies. Narayanan C, Bernard DN, Doucet N. Catalysts 6 (2016)
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  28. Mutations Proximal to Sites of Autoproteolysis and the α-Helix That Co-evolve under Drug Pressure Modulate the Autoprocessing and Vitality of HIV-1 Protease. Louis JM, Deshmukh L, Sayer JM, Aniana A, Clore GM. Biochemistry 54 5414-5424 (2015)
  29. Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance. Khan SN, Persons JD, Paulsen JL, Guerrero M, Schiffer CA, Kurt-Yilmaz N, Ishima R. Biochemistry 57 1652-1662 (2018)
  30. Atomistic simulations of the HIV-1 protease folding inhibition. Verkhivker G, Tiana G, Camilloni C, Provasi D, Broglia RA. Biophys J 95 550-562 (2008)
  31. Molecular dynamics simulations of HIV-1 protease monomer: Assembly of N-terminus and C-terminus into beta-sheet in water solution. Yan MC, Sha Y, Wang J, Xiong XQ, Ren JH, Cheng MS. Proteins 70 731-738 (2008)
  32. Novel macromolecular inhibitors of human immunodeficiency virus-1 protease. Miklóssy G, Tözsér J, Kádas J, Ishima R, Louis JM, Bagossi P. Protein Eng Des Sel 21 453-461 (2008)
  33. The maturation of HIV-1 protease precursor studied by discrete molecular dynamics. Kimura S, Caldarini M, Broglia RA, Dokholyan NV, Tiana G. Proteins 82 633-639 (2014)
  34. Enhanced stability of monomer fold correlates with extreme drug resistance of HIV-1 protease. Louis JM, Tözsér J, Roche J, Matúz K, Aniana A, Sayer JM. Biochemistry 52 7678-7688 (2013)
  35. Whiskers-less HIV-protease: a possible way for HIV-1 deactivation. Dayer MR, Dayer MS. J Biomed Sci 20 67 (2013)
  36. Predicting protein dynamics from structural ensembles. Copperman J, Guenza MG. J Chem Phys 143 243131 (2015)
  37. 1.8A X-ray structure of C95M/C1095F double mutant of tethered HIV-1 protease dimer complexed with acetyl pepstatin. Prashar V, Hosur MV. Biochem Biophys Res Commun 323 1229-1235 (2004)
  38. Denaturation of HIV-1 protease (PR) monomer by acetic acid: mechanistic and trajectory insights from molecular dynamics simulations and NMR. Borkar A, Borkar A, Rout MK, Hosur RV. J Biomol Struct Dyn 29 893-903 (2012)
  39. Fluctuating partially native-like topologies in the acid denatured ensemble of autolysis resistant HIV-1 protease. Rout MK, Hosur RV. Arch Biochem Biophys 482 33-41 (2009)
  40. Mode localization in the cooperative dynamics of protein recognition. Copperman J, Guenza MG. J Chem Phys 145 015101 (2016)
  41. A synergy of activity, stability, and inhibitor-interaction of HIV-1 protease mutants evolved under drug-pressure. Khan SN, Persons JD, Guerrero M, Ilina TV, Oda M, Ishima R. Protein Sci 30 571-582 (2021)
  42. Computational proteomics analysis of binding mechanisms and molecular signatures of the HIV-1 protease drugs. Verkhivker G. Artif Intell Med 45 197-206 (2009)
  43. Diverse Folding Pathways of HIV-1 Protease Monomer on a Rugged Energy Landscape. Yoo J, Louis JM, Chung HS. Biophys J 117 1456-1466 (2019)
  44. Probing the Interaction between HIV-1 Protease and the Homodimeric p66/p66' Reverse Transcriptase Precursor by Double Electron-Electron Resonance EPR Spectroscopy. Schmidt T, Louis JM, Clore GM. Chembiochem 21 3051-3055 (2020)
  45. Single point mutation induced alterations in the equilibrium structural transitions on the folding landscape of HIV-1 protease. Rout MK, Reddy JG, Phillips M, Hosur RV. J Biomol Struct Dyn 31 684-693 (2013)
  46. Crystal Structure of a Retroviral Polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT). Harrison JJEK, Tuske S, Das K, Ruiz FX, Bauman JD, Boyer PL, DeStefano JJ, Hughes SH, Arnold E. Viruses 13 (2021)
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