Gag-Pol polyprotein

Details

Name
Gag-Pol polyprotein
Synonyms
  • Pr160Gag-Pol
Gene Name
gag-pol
Organism
HIV-1
Amino acid sequence
>lcl|BSEQ0007296|Gag-Pol polyprotein
MGARASVLSGGELDRWEKIRLRPGGKKKYKLKHIVWASRELERFAVNPGLLETSEGCRQI
LGQLQPSLQTGSEELRSLYNTVATLYCVHQRIEIKDTKEALDKIEEEQNKSKKKAQQAAA
DTGHSSQVSQNYPIVQNIQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGAT
PQDLNTMLNTVGGHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTT
STLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFRDYVDRF
YKTLRAEQASQEVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKA
RVLAEAMSQVTNSATIMMQRGNFRNQRKIVKCFNCGKEGHIARNCRAPRKKGCWKCGKEG
HQMKDCTERQANFLREDLAFLQGKAREFSSEQTRANSPTISSEQTRANSPTRRELQVWGR
DNNSLSEAGADRQGTVSFNFPQITLWQRPLVTIKIGGQLKEALLDTGADDTVLEEMSLPG
RWKPKMIGGIGGFIKVRQYDQILIEICGHKAIGTVLVGPTPVNIIGRNLLTQIGCTLNFP
ISPIETVPVKLKPGMDGPKVKQWPLTEEKIKALVEICTEMEKEGKISKIGPENPYNTPVF
AIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLD
EDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIY
QYMDDLYVGSDLEIGQHRTKIEELRQHLLRWGLTTPDKKHQKEPPFLWMGYELHPDKWTV
QPIVLPEKDSWTVNDIQKLVGKLNWASQIYPGIKVRQLCKLLRGTKALTEVIPLTEEAEL
ELAENREILKEPVHGVYYDPSKDLIAEIQKQGQGQWTYQIYQEPFKNLKTGKYARTRGAH
TNDVKQLTEAVQKITTESIVIWGKTPKFKLPIQKETWETWWTEYWQATWIPEWEFVNTPP
LVKLWYQLEKEPIVGAETFYVDGAASRETKLGKAGYVTNRGRQKVVTLTDTTNQKTELQA
IHLALQDSGLEVNIVTDSQYALGIIQAQPDKSESELVNQIIEQLIKKEKVYLAWVPAHKG
IGGNEQVDKLVSAGIRKVLFLDGIDKAQDEHEKYHSNWRAMASDFNLPPVVAKEIVASCD
KCQLKGEAMHGQVDCSPGIWQLDCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFL
LKLAGRWPVKTIHTDNGSNFTSTTVKAACWWAGIKQEFGIPYNPQSQGVVESMNKELKKI
IGQVRDQAEHLKTAVQMAVFIHNFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQ
NFRVYYRDSRDPLWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCV
ASRQDED
Number of residues
1447
Molecular Weight
163278.36
Theoretical pI
9.02
GO Classification
Functions
aspartic-type endopeptidase activity / DNA binding / DNA-directed DNA polymerase activity / exoribonuclease H activity / lipid binding / RNA binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / structural molecule activity / zinc ion binding
Processes
DNA integration / DNA recombination / establishment of integrated proviral latency / induction by virus of host cysteine-type endopeptidase activity involved in apoptotic process / suppression by virus of host gene expression / viral entry into host cell / viral penetration into host nucleus / viral release from host cell
Components
host cell nucleus / host cell plasma membrane / host multivesicular body / viral nucleocapsid / virion membrane
General Function
Zinc ion binding
Specific Function
Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shutt off translation (By similarity).Matrix protein p17 targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus (By similarity). Matrix protein is part of the pre-integration complex. Implicated in the release from host cell mediated by Vpu. Binds to RNA (By similarity).Capsid protein p24: Forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry (By similarity). Host restriction factors such as TRIM5-alpha or TRIMCyp bind retroviral capsids and cause premature capsid disassembly, leading to blocks in reverse transcription. Capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species. Host PIN1 apparently facilitates the virion uncoating. On the other hand, interactions with PDZD8 or CYPA stabilize the capsid.Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced genomic RNA (gRNA). Binds these RNAs through its zinc fingers. Acts as a nucleic acid chaperone which is involved in rearangement of nucleic acid secondary structure during gRNA retrotranscription. Also facilitates template switch leading to recombination. As part of the polyprotein, participates to gRNA dimerization, packaging, tRNA incorporation and virion assembly.The aspartyl protease mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles. Hydrolyzes host EIF4GI and PABP1 in order to shut off the capped cellular mRNA translation. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response (By similarity).Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA(3)-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends (By similarity).Integrase: Catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Host cell membrane
Gene sequence
>lcl|BSEQ0007295|1539 bp
CGGAGGCTAGAAGGAGAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAG
ATCGATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAAAACATA
TAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACAT
CAGAAGGCTGTAGACAAATACTGGGACAGCTACAACCATCCCTTCAGACAGGATCAGAAG
AACTTAGATCATTATATAATACAGTAGCAACCCTCTATTGTGTGCATCAAAGGATAGAGA
TAAAAGACACCAAGGAAGCTTTAGACAAGATAGAGGAAGAGCAAAACAAAAGTAAGAAAA
AAGCACAGCAAGCAGCAGCTGACACAGGACACAGCAGCCAGGTCAGCCAAAATTACCCTA
TAGTGCAGAACATCCAGGGGCAAATGGTACATCAGGCCATATCACCTAGAACTTTAAATG
CATGGGTAAAAGTAGTAGAAGAGAAGGCTTTCAGCCCAGAAGTGATACCCATGTTTTCAG
CATTATCAGAAGGAGCCACCCCACAAGATTTAAACACCATGCTAAACACAGTGGGGGGAC
ATCAAGCAGCCATGCAAATGTTAAAAGAGACCATCAATGAGGAAGCTGCAGAATGGGATA
GAGTGCATCCAGTGCATGCAGGGCCTATTGCACCAGGCCAGATGAGAGAACCAAGGGGAA
GTGACATAGCAGGAACTACTAGTACCCTTCAGGAACAAATAGGATGGATGACAAATAATC
CACCTATCCCAGTAGGAGAAATTTATAAAAGATGGATAATCCTGGGATTAAATAAAATAG
TAAGAATGTATAGCCCTACCAGCATTCTGGACATAAGACAAGGACCAAAAGAACCCTTTA
GAGACTATGTAGACCGGTTCTATAAAACTCTAAGAGCCGAGCAAGCTTCACAGGAGGTAA
AAAATTGGATGACAGAAACCTTGTTGGTCCAAAATGCGAACCCAGATTGTAAGACTATTT
TAAAAGCATTGGGACCAGCAGCTACACTAGAAGAAATGATGACAGCATGTCAGGGAGTGG
GAGGACCCGGCCATAAGGCAAGAGTTTTGGCTGAAGCAATGAGCCAAGTAACAAATTCAG
CTACCATAATGATGCAAAGAGGCAATTTTAGGAACCAAAGAAAGATTGTTAAGTGTTTCA
ATTGTGGCAAAGAAGGGCACATAGCCAGAAATTGCAGGGCCCCTAGGAAAAAGGGCTGTT
GGAAATGTGGAAAGGAAGGACACCAAATGAAAGATTGTACTGAGAGACAGGCTAATTTTT
TAGGGAAGATCTGGCCTTCCTACAAGGGAAGGCCAGGGAATTTTCTTCAGAGCAGACCAG
AGCCAACAGCCCCACCATTTCTTCAGAGCAGACCAGAGCCAACAGCCCCACCAGAAGAGA
GCTTCAGGTCTGGGGTAGAGACAACAACTCCCTCTCAGAAGCAGGAGCCGATAGACAAGG
AACTGTATCCTTTAACTTCCCTCAGATCACTCTTTGGCA
Chromosome Location
Not Available
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP03367
UniProtKB Entry NamePOL_HV1BR
GenBank Protein ID326420
GenBank Gene IDK02013
General References
  1. Wain-Hobson S, Sonigo P, Danos O, Cole S, Alizon M: Nucleotide sequence of the AIDS virus, LAV. Cell. 1985 Jan;40(1):9-17. [Article]
  2. Alizon M, Wain-Hobson S, Montagnier L, Sonigo P: Genetic variability of the AIDS virus: nucleotide sequence analysis of two isolates from African patients. Cell. 1986 Jul 4;46(1):63-74. [Article]
  3. Gaedigk-Nitschko K, Schon A, Wachinger G, Erfle V, Kohleisen B: Cleavage of recombinant and cell derived human immunodeficiency virus 1 (HIV-1) Nef protein by HIV-1 protease. FEBS Lett. 1995 Jan 9;357(3):275-8. [Article]
  4. Khan MA, Akari H, Kao S, Aberham C, Davis D, Buckler-White A, Strebel K: Intravirion processing of the human immunodeficiency virus type 1 Vif protein by the viral protease may be correlated with Vif function. J Virol. 2002 Sep;76(18):9112-23. [Article]
  5. Vogt VM: Proteolytic processing and particle maturation. Curr Top Microbiol Immunol. 1996;214:95-131. [Article]
  6. Turner BG, Summers MF: Structural biology of HIV. J Mol Biol. 1999 Jan 8;285(1):1-32. [Article]
  7. Negroni M, Buc H: Mechanisms of retroviral recombination. Annu Rev Genet. 2001;35:275-302. [Article]
  8. Dunn BM, Goodenow MM, Gustchina A, Wlodawer A: Retroviral proteases. Genome Biol. 2002;3(4):REVIEWS3006. Epub 2002 Mar 26. [Article]
  9. Scarlata S, Carter C: Role of HIV-1 Gag domains in viral assembly. Biochim Biophys Acta. 2003 Jul 11;1614(1):62-72. [Article]
  10. Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ: The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie. 1991 Nov;73(11):1391-6. [Article]
  11. Arnold E, Jacobo-Molina A, Nanni RG, Williams RL, Lu X, Ding J, Clark AD Jr, Zhang A, Ferris AL, Clark P, et al.: Structure of HIV-1 reverse transcriptase/DNA complex at 7 A resolution showing active site locations. Nature. 1992 May 7;357(6373):85-9. [Article]
  12. Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC: Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. J Biol Chem. 1994 Oct 21;269(42):26344-8. [Article]
  13. Thaisrivongs S, Skulnick HI, Turner SR, Strohbach JW, Tommasi RA, Johnson PD, Aristoff PA, Judge TM, Gammill RB, Morris JK, Romines KR, Chrusciel RA, Hinshaw RR, Chong KT, Tarpley WG, Poppe SM, Slade DE, Lynn JC, Horng MM, Tomich PK, Seest EP, Dolak LA, Howe WJ, Howard GM, Watenpaugh KD, et al.: Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors. J Med Chem. 1996 Oct 25;39(22):4349-53. [Article]
  14. Silva AM, Cachau RE, Sham HL, Erickson JW: Inhibition and catalytic mechanism of HIV-1 aspartic protease. J Mol Biol. 1996 Jan 19;255(2):321-46. [Article]
  15. Weber IT, Wu J, Adomat J, Harrison RW, Kimmel AR, Wondrak EM, Louis JM: Crystallographic analysis of human immunodeficiency virus 1 protease with an analog of the conserved CA-p2 substrate -- interactions with frequently occurring glutamic acid residue at P2' position of substrates. Eur J Biochem. 1997 Oct 15;249(2):523-30. [Article]
  16. Wu J, Adomat JM, Ridky TW, Louis JM, Leis J, Harrison RW, Weber IT: Structural basis for specificity of retroviral proteases. Biochemistry. 1998 Mar 31;37(13):4518-26. [Article]
  17. Ringhofer S, Kallen J, Dutzler R, Billich A, Visser AJ, Scholz D, Steinhauser O, Schreiber H, Auer M, Kungl AJ: X-ray structure and conformational dynamics of the HIV-1 protease in complex with the inhibitor SDZ283-910: agreement of time-resolved spectroscopy and molecular dynamics simulations. J Mol Biol. 1999 Mar 5;286(4):1147-59. [Article]
  18. Dohnalek J, Hasek J, Duskova J, Petrokova H, Hradilek M, Soucek M, Konvalinka J, Brynda J, Sedlacek J, Fabry M: A distinct binding mode of a hydroxyethylamine isostere inhibitor of HIV-1 protease. Acta Crystallogr D Biol Crystallogr. 2001 Mar;57(Pt 3):472-6. [Article]
  19. Dohnalek J, Hasek J, Duskova J, Petrokova H, Hradilek M, Soucek M, Konvalinka J, Brynda J, Sedlacek J, Fabry M: Hydroxyethylamine isostere of an HIV-1 protease inhibitor prefers its amine to the hydroxy group in binding to catalytic aspartates. A synchrotron study of HIV-1 protease in complex with a peptidomimetic inhibitor. J Med Chem. 2002 Mar 28;45(7):1432-8. [Article]
  20. Skalova T, Hasek J, Dohnalek J, Petrokova H, Buchtelova E, Duskova J, Soucek M, Majer P, Uhlikova T, Konvalinka J: An ethylenamine inhibitor binds tightly to both wild type and mutant HIV-1 proteases. Structure and energy study. J Med Chem. 2003 Apr 24;46(9):1636-44. [Article]
  21. Petrokova H, Duskova J, Dohnalek J, Skalova T, Vondrackova-Buchtelova E, Soucek M, Konvalinka J, Brynda J, Fabry M, Sedlacek J, Hasek J: Role of hydroxyl group and R/S configuration of isostere in binding properties of HIV-1 protease inhibitors. Eur J Biochem. 2004 Nov;271(22):4451-61. [Article]
  22. Vega S, Kang LW, Velazquez-Campoy A, Kiso Y, Amzel LM, Freire E: A structural and thermodynamic escape mechanism from a drug resistant mutation of the HIV-1 protease. Proteins. 2004 May 15;55(3):594-602. [Article]
  23. Brynda J, Rezacova P, Fabry M, Horejsi M, Stouracova R, Sedlacek J, Soucek M, Hradilek M, Lepsik M, Konvalinka J: A phenylnorstatine inhibitor binding to HIV-1 protease: geometry, protonation, and subsite-pocket interactions analyzed at atomic resolution. J Med Chem. 2004 Apr 8;47(8):2030-6. [Article]
  24. Tie Y, Boross PI, Wang YF, Gaddis L, Hussain AK, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT: High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. J Mol Biol. 2004 Apr 23;338(2):341-52. [Article]
  25. Mahalingam B, Wang YF, Boross PI, Tozser J, Louis JM, Harrison RW, Weber IT: Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site. Eur J Biochem. 2004 Apr;271(8):1516-24. [Article]
  26. Clemente JC, Moose RE, Hemrajani R, Whitford LR, Govindasamy L, Reutzel R, McKenna R, Agbandje-McKenna M, Goodenow MM, Dunn BM: Comparing the accumulation of active- and nonactive-site mutations in the HIV-1 protease. Biochemistry. 2004 Sep 28;43(38):12141-51. [Article]
  27. Brynda J, Rezacova P, Fabry M, Horejsi M, Stouracova R, Soucek M, Hradilek M, Konvalinka J, Sedlacek J: Inhibitor binding at the protein interface in crystals of a HIV-1 protease complex. Acta Crystallogr D Biol Crystallogr. 2004 Nov;60(Pt 11):1943-8. Epub 2004 Oct 20. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB07327R-95845experimentalunknownDetails
DB07505N-({(3R,4R)-4-[(benzyloxy)methyl]pyrrolidin-3-yl}methyl)-N-(2-methylpropyl)benzenesulfonamideexperimentalunknownDetails
DB080413-BENZYLOXYCARBONYLAMINO-2-HYDROXY-4-PHENYL-BUTYRIC ACIDexperimentalunknownDetails
DB084283(S)-AMINO-4-PHENYL-BUTAN-2(S)-OLexperimentalunknownDetails
DB086623-[1-(4-BROMO-PHENYL)-2-METHYL-PROPYL]-4-HYDROXY-CHROMEN-2-ONEexperimentalunknownDetails