HIV-1 protease

HIV-1 protease

Protein
Name = HIV-1 Protease
caption = HIV-1 protease (blue) complexed with inhibitor (yellow) based on PDB|1EBZ



HGNCid =
Symbol = HIV PR
AltSymbols =
EntrezGene =
OMIM =
RefSeq =
UniProt = P03366
PDB = 1EBZ
ECnumber = 3.4.23
Chromosome =
Arm =
Band =
LocusSupplementaryData =

HIV-1 protease (HIV PR) is an aspartic protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.cite journal | author = Davies DR | title = The structure and function of the aspartic proteinases | journal = Annu Rev Biophys Biophys Chem | volume = 19 | issue = | pages = 189–215 | year = 1990 | pmid = 2194475 | doi = 10.1146/annurev.bb.19.060190.001201 | url = ] cite journal | author = Brik A, Wong CH | title = HIV-1 protease: mechanism and drug discovery | journal = Org. Biomol. Chem. | volume = 1 | issue = 1 | pages = 5–14 | year = 2003 | month = January | pmid = 12929379 | url = | doi = 10.1039/b208248a ] 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.cite journal | author = Kräusslich HG, Ingraham RH, Skoog MT, Wimmer E, Pallai PV, Carter CA | title = Activity of purified biosynthetic proteinase of human immunodeficiency virus on natural substrates and synthetic peptides | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 86 | issue = 3 | pages = 807–11 | year = 1989 | month = February | pmid = 2644644 | pmc = 286566 | url = | doi = 10.1073/pnas.86.3.807 ] cite journal | author = Kohl NE, Emini EA, Schleif WA, "et al" | title = Active human immunodeficiency virus protease is required for viral infectivity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 13 | pages = 4686–90 | year = 1988 | month = July | pmid = 3290901 | pmc = 280500 | url = | doi = 10.1073/pnas.85.13.4686 ] Thus, mutation of HIV PR’s active site or inhibition of its activity disrupts HIV’s ability to replicate and infect additional cells,cite journal | author = Seelmeier S, Schmidt H, Turk V, von der Helm K | title = Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 18 | pages = 6612–6 | year = 1988 | month = September | pmid = 3045820 | pmc = 282027 | url = | doi = 10.1073/pnas.85.18.6612 ] making HIV PR inhibition the subject of much pharmaceutical research.cite journal | author = McPhee F, Good AC, Kuntz ID, Craik CS | title = Engineering human immunodeficiency virus 1 protease heterodimers as macromolecular inhibitors of viral maturation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 21 | pages = 11477–81 | year = 1996 | month = October | pmid = 8876160 | pmc = 56635 | url = | doi = 10.1073/pnas.93.21.11477 ]

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.cite journal | author = Davies DR | title = The structure and function of the aspartic proteinases | journal = Annu Rev Biophys Biophys Chem | volume = 19 | issue = | pages = 189–215 | year = 1990 | pmid = 2194475 | doi = 10.1146/annurev.bb.19.060190.001201 | url = ] The active site lies between the identical subunits and has the characteristic Asp-Thr-Gly (Asp25, Thr26 and Gly27) sequence common to aspartic proteases. The two Asp25 residues (one from each chain) act as the catalytic residues. According to the mechanism for HIV PR protein cleavage proposed by Jaskolski et al., water acts as a nucleophile, which acts in simultaneous conjunction with a well-placed aspartic acid to hydrolyze the scissile peptide bond.cite journal | author =Jaskólski M, Tomasselli AG, Sawyer TK, Staples DG, Heinrikson RL, Schneider J, Kent SB, Wlodawer A | title = Structure at 2.5-A resolution of chemically synthesized human immunodeficiency virus type 1 protease complexed with a hydroxyethylene-based inhibitor | journal = Biochemistry | volume = 30 | issue = 6 | pages = 1600–9 | year = 1991 | month = February | pmid = 1993177 | url = | doi = 10.1021/bi00220a023 ] Additionally, HIV PR has two molecular “flaps” which move a distance of up to 7 Å when the enzyme becomes associated with a substrate.cite journal | author = Miller M, Schneider J, Sathyanarayana BK, Toth MV, Marshall GR, Clawson L, Selk L, Kent SB, Wlodawer A | title = Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution | journal = Science (journal) | volume = 246 | issue = 4934 | pages = 1149–52 | year = 1989 | month = December | pmid = 2686029 | url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=2686029 | issn = ]

Topology

Perryman et al. have proposed terminology for parts of HIV PR based on its resemblance to an English Bulldog.cite journal | author = Perryman AL, Lin JH, McCammon JA | title = HIV-1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: possible contributions to drug resistance and a potential new target site for drugs | journal = Protein Sci. | volume = 13 | issue = 4 | pages = 1108–23 | year = 2004 | month = April | pmid = 15044738 | pmc = 2280056 | doi = 10.1110/ps.03468904 | url = http://ai.stanford.edu/~serafim/CS374_2005/Papers/MolecularDynamics_DrugResistance.pdf|format=|accessdate=2008-06-27 ]

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. However, due to the high mutation rates of retroviruses, and considering that a single amino acid 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.cite journal | author = Watkins T, Resch W, Irlbeck D, Swanstrom R | title = Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors | journal = Antimicrob. Agents Chemother. | volume = 47 | issue = 2 | pages = 759–69 | year = 2003 | month = February | pmid = 12543689 | pmc = 151730 | url = | doi = 10.1128/AAC.47.2.759-769.2003 ] 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, cDNA integration and virion assembly.cite journal | author = Moore JP, Stevenson M | title = New targets for inhibitors of HIV-1 replication | journal = Nat. Rev. Mol. Cell Biol. | volume = 1 | issue = 1 | pages = 40–9 | year = 2000 | month = October | pmid = 11413488 | doi = 10.1038/35036060 | url = ] cite journal | author = De Clercq E | title = The design of drugs for HIV and HCV | journal = Nat Rev Drug Discov | volume = 6 | issue = 12 | pages = 1001–18 | year = 2007 | month = December | pmid = 18049474 | doi = 10.1038/nrd2424 | url = ]

External links

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References


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