Gag-Pol polyprotein

Details

Name
Gag-Pol polyprotein
Synonyms
  • Pr160Gag-Pol
Gene Name
gag-pol
Organism
HIV-2
Amino acid sequence
>lcl|BSEQ0003434|Gag-Pol polyprotein
MGARNSVLRGKKADELERIRLRPGGKKKYRLKHIVWAANKLDRFGLAESLLESKEGCQKI
LTVLDPMVPTGSENLKSLFNTVCVIWCIHAEEKVKDTEGAKQIVRRHLVAETGTAEKMPS
TSRPTAPSSEKGGNYPVQHVGGNYTHIPLSPRTLNAWVKLVEEKKFGAEVVPGFQALSEG
CTPYDINQMLNCVGDHQAAMQIIREIINEEAAEWDVQHPIPGPLPAGQLREPRGSDIAGT
TSTVEEQIQWMFRPQNPVPVGNIYRRWIQIGLQKCVRMYNPTNILDIKQGPKEPFQSYVD
RFYKSLRAEQTDPAVKNWMTQTLLVQNANPDCKLVLKGLGMNPTLEEMLTACQGVGGPGQ
KARLMAEALKEVIGPAPIPFAAAQQRKAFKCWNCGKEGHSARQCRAPRRQGCWKCGKPGH
IMTNCPDRQAGFLRTGPLGKEAPQLPRGPSSAGADTNSTPSGSSSGSTGEIYAAREKTER
AERETIQGSDRGLTAPRAGGDTIQGATNRGLAAPQFSLWKRPVVTAYIEGQPVEVLLDTG
ADDSIVAGIELGNNYSPKIVGGIGGFINTKEYKNVEIEVLNKKVRATIMTGDTPINIFGR
NILTALGMSLNLPVAKVEPIKIMLKPGKDGPKLRQWPLTKEKIEALKEICEKMEKEGQLE
EAPPTNPYNTPTFAIKKKDKNKWRMLIDFRELNKVTQDFTEIQLGIPHPAGLAKKRRITV
LDVGDAYFSIPLHEDFRPYTAFTLPSVNNAEPGKRYIYKVLPQGWKGSPAIFQHTMRQVL
EPFRKANKDVIIIQYMDDILIASDRTDLEHDRVVLQLKELLNGLGFSTPDEKFQKDPPYH
WMGYELWPTKWKLQKIQLPQKEIWTVNDIQKLVGVLNWAAQLYPGIKTKHLCRLIRGKMT
LTEEVQWTELAEAELEENRIILSQEQEGHYYQEEKELEATVQKDQENQWTYKIHQEEKIL
KVGKYAKVKNTHTNGIRLLAQVVQKIGKEALVIWGRIPKFHLPVEREIWEQWWDNYWQVT
WIPDWDFVSTPPLVRLAFNLVGDPIPGAETFYTDGSCNRQSKEGKAGYVTDRGKDKVKKL
EQTTNQQAELEAFAMALTDSGPKVNIIVDSQYVMGISASQPTESESKIVNQIIEEMIKKE
AIYVAWVPAHKGIGGNQEVDHLVSQGIRQVLFLEKIEPAQEEHEKYHSNVKELSHKFGIP
NLVARQIVNSCAQCQQKGEAIHGQVNAELGTWQMDCTHLEGKIIIVAVHVASGFIEAEVI
PQESGRQTALFLLKLASRWPITHLHTDNGANFTSQEVKMVAWWIGIEQSFGVPYNPQSQG
VVEAMNHHLKNQISRIREQANTIETIVLMAIHCMNFKRRGGIGDMTPSERLINMITTEQE
IQFLQAKNSKLKDFRVYFREGRDQLWKGPGELLWKGEGAVLVKVGTDIKIIPRRKAKIIR
DYGGRQEMDSGSHLEGAREDGEMA
Number of residues
1464
Molecular Weight
164644.035
Theoretical pI
8.67
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 / 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: Mediates, with Gag polyrotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spherical particles, recruiting the viral Env proteins, and packaging the genomic RNA via direct interactions with the RNA packaging sequence (Psi). Gag-Pol polyprotein may regulate its own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, the polyprotein would promote translation, whereas at high concentration, the polyprotein would encapsidate genomic RNA and then shutt off translation.Matrix protein p17: Targets the polyprotein to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. Matrix protein is part of the pre-integration complex. Implicated in the release from host cell mediated by Vpu. Binds to RNA.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.Protease: Aspartyl protease that 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: 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.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
Chromosome Location
Not Available
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP04584
UniProtKB Entry NamePOL_HV2RO
GenBank Gene IDX05291
General References
  1. Guyader M, Emerman M, Sonigo P, Clavel F, Montagnier L, Alizon M: Genome organization and transactivation of the human immunodeficiency virus type 2. Nature. 1987 Apr 16-22;326(6114):662-9. [Article]
  2. Vogt VM: Proteolytic processing and particle maturation. Curr Top Microbiol Immunol. 1996;214:95-131. [Article]
  3. Turner BG, Summers MF: Structural biology of HIV. J Mol Biol. 1999 Jan 8;285(1):1-32. [Article]
  4. Negroni M, Buc H: Mechanisms of retroviral recombination. Annu Rev Genet. 2001;35:275-302. [Article]
  5. Dunn BM, Goodenow MM, Gustchina A, Wlodawer A: Retroviral proteases. Genome Biol. 2002;3(4):REVIEWS3006. Epub 2002 Mar 26. [Article]
  6. Gustchina A, Weber IT: Comparative analysis of the sequences and structures of HIV-1 and HIV-2 proteases. Proteins. 1991;10(4):325-39. [Article]
  7. Tong L, Pav S, Pargellis C, Do F, Lamarre D, Anderson PC: Crystal structure of human immunodeficiency virus (HIV) type 2 protease in complex with a reduced amide inhibitor and comparison with HIV-1 protease structures. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8387-91. [Article]
  8. Mulichak AM, Hui JO, Tomasselli AG, Heinrikson RL, Curry KA, Tomich CS, Thaisrivongs S, Sawyer TK, Watenpaugh KD: The crystallographic structure of the protease from human immunodeficiency virus type 2 with two synthetic peptidic transition state analog inhibitors. J Biol Chem. 1993 Jun 25;268(18):13103-9. [Article]
  9. 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]
  10. Priestle JP, Fassler A, Rosel J, Tintelnot-Blomley M, Strop P, Grutter MG: Comparative analysis of the X-ray structures of HIV-1 and HIV-2 proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor. Structure. 1995 Apr 15;3(4):381-9. [Article]
  11. Tong L, Pav S, Mui S, Lamarre D, Yoakim C, Beaulieu P, Anderson PC: Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere. Structure. 1995 Jan 15;3(1):33-40. [Article]
  12. Thaisrivongs S, Watenpaugh KD, Howe WJ, Tomich PK, Dolak LA, Chong KT, Tomich CC, Tomasselli AG, Turner SR, Strohbach JW, et al.: Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors. J Med Chem. 1995 Sep 1;38(18):3624-37. [Article]
  13. Romines KR, Watenpaugh KD, Tomich PK, Howe WJ, Morris JK, Lovasz KD, Mulichak AM, Finzel BC, Lynn JC, Horng MM, et al.: Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors. J Med Chem. 1995 May 26;38(11):1884-91. [Article]
  14. Beaulieu PL, Wernic D, Abraham A, Anderson PC, Bogri T, Bousquet Y, Croteau G, Guse I, Lamarre D, Liard F, Paris W, Thibeault D, Pav S, Tong L: Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere. J Med Chem. 1997 Jul 4;40(14):2164-76. [Article]
  15. Eijkelenboom AP, van den Ent FM, Vos A, Doreleijers JF, Hard K, Tullius TD, Plasterk RH, Kaptein R, Boelens R: The solution structure of the amino-terminal HHCC domain of HIV-2 integrase: a three-helix bundle stabilized by zinc. Curr Biol. 1997 Oct 1;7(10):739-46. [Article]
  16. Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK: Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14410-5. Epub 2002 Oct 17. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02428Quinaldic AcidexperimentalunknownDetails
DB044903-(Mercaptomethylene)PyridineexperimentalunknownDetails
DB075815-AMINO-6-CYCLOHEXYL-4-HYDROXY-2-ISOPROPYL-HEXANOIC ACIDexperimentalunknownDetails
DB07634(2,6-Dimethylphenoxy)acetic acidexperimentalunknownDetails
DB08231Myristic acidexperimentalunknownDetails
DB082746,7,8,9-TETRAHYDRO-4-HYDROXY-3-(1-PHENYLPROPYL)CYCLOHEPTA[B]PYRAN-2-ONEexperimentalunknownDetails
DB082861-Naphthoxyacetic acidexperimentalunknownDetails
DB08421PIPERIDINE-2-CARBOXYLIC ACID TERT-BUTYLAMIDEexperimentalunknownDetails
DB084743-(CARBOXYAMIDE(2-CARBOXYAMIDE-2-TERTBUTYLETHYL))PENTANexperimentalunknownDetails
DB086634-HYDROXY-7-METHOXY-3-(1-PHENYL-PROPYL)-CHROMEN-2-ONEexperimentalunknownDetails
DB08664({3-[1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-propyl]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl esterexperimentalunknownDetails
DB086865,6,7,8,9,10-HEXAHYDRO-4-HYDROXY-3-(1-PHENYLPROPYL)CYCLOOCTA[B]PYRAN-2-ONEexperimentalunknownDetails