My watch list  

HIV-1 protease

HIV-1 Protease (blue) complexed with inhibitor (yellow)
HIV-1 Protease
Symbol HIV PR
Other data
EC number 3.4.23

HIV-1 protease (HIV PR) is an aspartic protease that is essential for the life-cycle of HIV, a retrovirus.[1] HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion. Without effective HIV PR, HIV virions remain uninfectious.[2] Thus, mutation of HIV PR’s active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells,[3] making HIV PR inhibition the subject of much pharmaceutical research. [4]



Structure and function

HIV PR's protein structure has been investigated using X-ray crystallography. It exists as a homodimer, with each subunit made up of 99 amino acids. [5] The active site lies between the identical subunits and has the characteristic Asp-Thr-Gly sequence common to aspartic proteases (see Figures 1-3). A mechanism for HIV PR protein cleavage proposed by Jaskolski et al. is seen below in Figure 4.[6] In this mechanism, water acts as a nucleophile which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond. Additionally, HIV PR has two molecular “flaps” which move a distance of up to 7Å when the enzyme becomes associated with a substrate (see Figures 1, 3 and 6).[7]

HIV-1 protease as a drug target

With its integral role in HIV replication, HIV PR has been a prime target for drug therapy. HIV PR inhibitors work by specifically binding to the active site by mimicking the tetrahedral intermediate of its substrate and essentially becoming “stuck,” disabling the enzyme (see Figures 1 and 2). However, due to the high mutation rates of retroviruses, and considering that a single nucleotide change within HIV PR can render it invisible to an inhibitor, the active site of this enzyme can change rapidly when under the selective pressure of replication-inhibiting drugs.[8]One approach to minimizing the development of drug-resistance in HIV is to administer a drug cocktail comprised of drugs which inhibit several key aspects of HIV’s replication cycle simultaneously, rather than one drug at a time. Other drug therapy targets include reverse transcriptase, virus attachment, membrane fusion, genetic integration and virion assembly.[9]


As illustrated by a comparison of Figures 5 and 6, HIV PR has one more noteworthy attribute: its remarkable resemblance to an English Bulldog.    


  1. ^ Davies, D. R. The Structure and Function of the Aspartic Proteinases. Annual Review of Biophysics and Biophysical Chemistry. June 1990. Vol. 19: 189-215; Brik, A. and Wong C.H. HIV-1 protease: mechanism and drug discovery. Org. Biomol. Chem. 1 (1): (2003). 5-14.
  2. ^ Krausslich, H.G., R.H. Ingraham, M.T. Skoog, E. Wimmer, P.V. Pallai and C.A. Carter. Activity of purified biosynthetic proteinase of human immunodeficiency virus on natural substrates and synthetic peptides. Proc. Natl. Acad. Sci. USA. February 1989; 86(3): 807–811.; Kohl, N.E., E.A. Emini, W.A. Schleif, L.J. Davis, J.C. Davis, J.C. Heimbach, R.A.F. Dixon, E.M. Scolnick and I.S. Sigal. Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl. Acad. Sci. USA, 1988, 85, 4686.
  3. ^ Seelmeier, Sigrid, Holger Schmidt, Vito Turk and Klaus Von Der Helm. Human Immunodeficiency Virus Has an Aspartic-Type Protease that Can Be Inhibited by Pepstatin A. Proceedings of the National Academy of Sciences of the United States of America. Vol. 85, No. 18. (Sep. 15, 1988), pp. 6612-6616.
  4. ^ McPhee, Fiona, Andrew C. Good, Irwin D. Kuntz and Charles S. Craik. Engineering Human Immunodeficiency Virus 1 Protease Heterodimers as Macromolecular Inhibitors of Viral Maturation. Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 21. (Oct. 15, 1996), pp. 11477-11482.
  5. ^ Davies, D. R. The Structure and Function of the Aspartic Proteinases. Annual Review of Biophysics and Biophysical Chemistry. June 1990. Vol. 19: 189-215.
  6. ^ Jaskolski, M., A.G. Tomasselli, T.K. Sawyer, D.G. Staples, R.L. Heinrikson, J. Schneider, S.B.H. Kent and A. Wlodawer. Structure at 2.5-A Resolution of Chemically Synthesized Human Immunodeficiency Virus Type 1 Protease Complexed with a Hydroxyethylene-Based Inhibitor. Biochemistry, 1991, 30, 1600.
  7. ^ Miller, M, J. Schneider, B.K. Sathyanarayana, M.V. Toth, G.R. Marshall, L. Clawson, L. Selk, S. Kent and A. Wlodawer. Structure of Complex of Synthetic HIV-1 Protease with a Substrate-Based Inhibitor at 2.3 A Resolution. Science. New Series, Vol. 246, No. 4934. (Dec. 1, 1989), pp. 1149-1152.
  8. ^ Watkins, Terri, Wolfgang Resch, David Irlbeck and Ronald Swanstrom. Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors. Antimicrobial Agents and Chemotherapy, February 2003, p. 759-769, Vol. 47, No. 2.
  9. ^ Moore, John P. and Mario Stevenson. New Targets for Inhibitors of HIV-1 Replication. Molecular Cell Biology. Vol. 1: October 2000. pp. 40-49.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "HIV-1_protease". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE