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Effects of remote mutation on the autolysis of HIV-1 PR: X-ray and NMR investigations.

Kumar M, Kannan KK, Hosur MV, Bhavesh NS, Chatterjee A, Mittal R, Hosur RV
Biochem Biophys Res Commun 294 395-401 (2002)
Cited: 18 times
EuropePMC logo PMID: 12051725

Abstract

Autolysis rates of the C95M and C95M/C1095A mutants of a HIV-1 protease tethered dimer have been determined by real time NMR and it is observed that the double mutant has approximately two times higher rate. X-ray structure of the C95M/C1095A double mutant has been solved and refined to 2.1 A resolution. Comparison of the double mutant structure with that of C95M single mutant reveals that there is a shift in the position of the catalytic aspartates and the bound catalytic water. The mutation also causes a loss of hydrophobic packing near the dimerization domain of the protein. These observations demonstrate that subtle changes are adequate to cause significant changes in the rate of autolysis of the double mutant. This provides a rationale for the effects of remote mutations on the activity and drug resistance of the enzyme.

Reviews - 1lv1 mentioned but not cited (1)

  1. An overview of the Plasmodium falciparum hexose transporter and its therapeutic interventions. Jiang X. Proteins 90 1766-1778 (2022)

Articles - 1lv1 mentioned but not cited (6)

  1. Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates. Das A, Prashar V, Mahale S, Serre L, Ferrer JL, Hosur MV. Proc Natl Acad Sci U S A 103 18464-18469 (2006)
  2. Observation of a tetrahedral reaction intermediate in the HIV-1 protease-substrate complex. Kumar M, Prashar V, Mahale S, Hosur MV. Biochem J 389 365-371 (2005)
  3. Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes. Robbins AH, Coman RM, Bracho-Sanchez E, Fernandez MA, Gilliland CT, Li M, Agbandje-McKenna M, Wlodawer A, Dunn BM, McKenna R. Acta Crystallogr D Biol Crystallogr 66 233-242 (2010)
  4. Mining the protein data bank to differentiate error from structural variation in clustered static structures: an examination of HIV protease. Venkatakrishnan B, Palii ML, Agbandje-McKenna M, McKenna R. Viruses 4 348-362 (2012)
  5. Catalytic water co-existing with a product peptide in the active site of HIV-1 protease revealed by X-ray structure analysis. Prashar V, Bihani S, Das A, Ferrer JL, Hosur M. PLoS One 4 e7860 (2009)
  6. Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using Neutrons: Implications for the Catalytic Mechanism and Drug Design. Kumar M, Mandal K, Blakeley MP, Wymore T, Kent SBH, Louis JM, Das A, Kovalevsky A. ACS Omega 5 11605-11617 (2020)


Reviews citing this publication (1)

  1. Linkers in the structural biology of protein-protein interactions. Reddy Chichili VP, Kumar V, Sivaraman J. Protein Sci 22 153-167 (2013)

Articles citing this publication (10)

  1. New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies. Farid R, Day T, Friesner RA, Pearlstein RA. Bioorg Med Chem 14 3160-3173 (2006)
  2. Controlling the enantioselectivity of enzymes by directed evolution: practical and theoretical ramifications. Reetz MT. Proc Natl Acad Sci U S A 101 5716-5722 (2004)
  3. Directed evolution of enantioselective enzymes: iterative cycles of CASTing for probing protein-sequence space. Reetz MT, Wang LW, Bocola M. Angew Chem Int Ed Engl 45 1236-1241 (2006)
  4. Learning from directed evolution: Further lessons from theoretical investigations into cooperative mutations in lipase enantioselectivity. Reetz MT, Puls M, Carballeira JD, Vogel A, Jaeger KE, Eggert T, Thiel W, Bocola M, Otte N. Chembiochem 8 106-112 (2007)
  5. Learning from directed evolution: theoretical investigations into cooperative mutations in lipase enantioselectivity. Bocola M, Otte N, Jaeger KE, Reetz MT, Thiel W. Chembiochem 5 214-223 (2004)
  6. 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)
  7. Adaptability and flexibility of HIV-1 protease. Kumar M, Hosur MV. Eur J Biochem 270 1231-1239 (2003)
  8. 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)
  9. Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition. Kulp JL, Cloudsdale IS, Kulp JL, Guarnieri F. PLoS One 12 e0183327 (2017)
  10. Following autolysis in proteases by NMR: insights into multiple unfolding pathways and mutational plasticities. Chatterjee A, Hosur RV. Biophys Chem 123 1-10 (2006)


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