| IED ID | IndEnz0002001910 |
| Enzyme Type ID | protease001910 |
| Protein Name |
Gag-Pol polyprotein Pr160Gag-Pol Cleaved into: Matrix protein p17 MA ; Capsid protein p24 CA ; Spacer peptide 1 SP1 p2 ; Nucleocapsid protein p7 NC ; Transframe peptide TF ; p6-pol p6* ; Protease EC 3.4.23.16 PR Retropepsin ; Reverse transcriptase/ribonuclease H EC 2.7.7.49 EC 2.7.7.7 EC 3.1.26.13 Exoribonuclease H EC 3.1.13.2 p66 RT ; p51 RT; p15; Integrase IN EC 2.7.7.- EC 3.1.-.- |
| Gene Name | gag-pol |
| Organism | Human immunodeficiency virus type 1 group M subtype G (isolate SE6165) (HIV-1) |
| Taxonomic Lineage | Viruses Riboviria Pararnavirae Artverviricota Revtraviricetes Ortervirales Retroviridae Orthoretrovirinae Lentivirus Human immunodeficiency virus 1 HIV-1 group M HIV-1 M:G Human immunodeficiency virus type 1 group M subtype G (isolate SE6165) (HIV-1) |
| Enzyme Sequence | MGARASVLTGGKLDAWEKIRLRPGGRKSYKIKHLVWASRELERFALNPDLLETAEGCQQIMRQLQPSLQTGTEEIKSLYNAVATLYCVHQRIEVKDTKEALEEVEKIQKKSQEKIQQAAMDKGNSNQVSQNYPIVQNAQGQMVHQAITPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNLMLNTVGGHQAAMQMLKDTINEEAAEWDRMHPQQAGPFPPGQIREPRGSDIAGTTSSLQEQITWMTGNPPIPVGEIYKRWIILGLNKIVRMYSPVSILDIRQGPKEPFRDYVDRFFKCLRAEQASQDVKGWMTDTLLVQNANPDCKTILRALGQGASLEEMMTACQGVGGPSHKARVLAEAMSQASGAAAAIMMQRSNFKGPRRTIKCFNCGKEGHLARNCRAPRKKGCWKCGKEGHQMKDCTERQANFFRENLAFQQGEAREFSSEQDRTNSPTCRKPRVRRGDSPLPEAGDEGKGAISLPQITLWQRPLVTVKIGGQLIEALLDTGADDTVLEEINLPGRWKPKMIGGIGGFIKVRQYDQVPIEISGKKAIGTILVGPTPINIIGRNMLTQIGCTLNFPISPIETVPVKLKPGMDGPRVKQWPLTEEKIKALTEICKEMEEEGKISKIGPENPYNTPIFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLDEDFRKYTAFTIPSINNETPGVRYQYNVLPQGWKGSPAIFQSSMTRILEPFRANNPEMVIYQYMDDLYVGSDLEIGQHRAKIEELREHLLKWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQPIQLPDKESWTVNDIQKLVGKLNWASQIYPGIKVTHLCKLLRGAKALTDIVSLTAEAEMELAENREILREPVHGVYYDPSKELIAEVQKQGLDQWTYQIYQEPYKNLKTGKYAKRGSAHTNDVKQLTEVVQKIATESIVIWGKTPKFKLPIRKETWEIWWTDYWQATWIPEWEFVNTPPLVKLWYRLETEPIPGAETYYVDGAANRETKLGKAGYVTDKGKQKIITLTETTNQKAELQAIQLALQDSRSEVNIVTDSQYALGIIQAQPDRSEAELVNQIIEQLIKKEKVYLSWVPAHKGIGGNEQVDKLVSSGIRKVLFLDGIDKAQEEHERYHNNWRAMASDFNLPPIVAKEIVASCDKCQLKGEAMHGQVDCSPGIWQLDCTHLEGKIIIVAVHVASGYIEAEVIPAETGQETAYFILKLAGRWPVTVIHTDNGSNFTSAAVKAACWWANITQEFGIPYNPQSQGVVESMNKELKKIIGQVRDQAEHLKTAVQMAVFIHNFKRKGGIGGYSAGERIIDIIASDIQTKELQKQITKIQNFRVYYRDSRDPVWKGPAKLLWKGEGAVVIQDNNEIKVVPRRKAKIIRDYGKQMAGDDCVAGRQDED |
| Enzyme Length | 1433 |
| Uniprot Accession Number | O89940 |
| Absorption | |
| Active Site | ACT_SITE 511; /note=For protease activity; shared with dimeric partner; /evidence=ECO:0000255|PROSITE-ProRule:PRU10094 |
| Activity Regulation | ACTIVITY REGULATION: Protease: The viral protease is inhibited by many synthetic protease inhibitors (PIs), such as amprenavir, atazanavir, indinavir, loprinavir, nelfinavir, ritonavir and saquinavir. Use of protease inhibitors in tritherapy regimens permit more ambitious therapeutic strategies. Reverse transcriptase/ribonuclease H: RT can be inhibited either by nucleoside RT inhibitors (NRTIs) or by non nucleoside RT inhibitors (NNRTIs). NRTIs act as chain terminators, whereas NNRTIs inhibit DNA polymerization by binding a small hydrophobic pocket near the RT active site and inducing an allosteric change in this region. Classical NRTIs are abacavir, adefovir (PMEA), didanosine (ddI), lamivudine (3TC), stavudine (d4T), tenofovir (PMPA), zalcitabine (ddC), and zidovudine (AZT). Classical NNRTIs are atevirdine (BHAP U-87201E), delavirdine, efavirenz (DMP-266), emivirine (I-EBU), and nevirapine (BI-RG-587). The tritherapies used as a basic effective treatment of AIDS associate two NRTIs and one NNRTI. {ECO:0000250}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.; EC=3.4.23.16; Evidence={ECO:0000255|PROSITE-ProRule:PRU00275}; CATALYTIC ACTIVITY: Reaction=Endohydrolysis of RNA in RNA/DNA hybrids. Three different cleavage modes: 1. sequence-specific internal cleavage of RNA. Human immunodeficiency virus type 1 and Moloney murine leukemia virus enzymes prefer to cleave the RNA strand one nucleotide away from the RNA-DNA junction. 2. RNA 5'-end directed cleavage 13-19 nucleotides from the RNA end. 3. DNA 3'-end directed cleavage 15-20 nucleotides away from the primer terminus.; EC=3.1.26.13; Evidence={ECO:0000250}; CATALYTIC ACTIVITY: Reaction=3'-end directed exonucleolytic cleavage of viral RNA-DNA hybrid.; EC=3.1.13.2; Evidence={ECO:0000250}; CATALYTIC ACTIVITY: Reaction=a 2'-deoxyribonucleoside 5'-triphosphate + DNA(n) = diphosphate + DNA(n+1); Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, Rhea:RHEA-COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:173112; EC=2.7.7.49; Evidence={ECO:0000255|PROSITE-ProRule:PRU00405}; CATALYTIC ACTIVITY: Reaction=a 2'-deoxyribonucleoside 5'-triphosphate + DNA(n) = diphosphate + DNA(n+1); Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, Rhea:RHEA-COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:173112; EC=2.7.7.7; Evidence={ECO:0000255|PROSITE-ProRule:PRU00405}; |
| DNA Binding | DNA_BIND 1368..1415; /note=Integrase-type; /evidence=ECO:0000255|PROSITE-ProRule:PRU00506 |
| EC Number | 3.4.23.16; 2.7.7.49; 2.7.7.7; 3.1.26.13; 3.1.13.2; 2.7.7.-; 3.1.-.- |
| Enzyme Function | FUNCTION: [Gag-Pol polyprotein]: Mediates, with Gag polyprotein, 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 shut off translation. {ECO:0000250}.; FUNCTION: [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. {ECO:0000250|UniProtKB:P12497}.; FUNCTION: [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. {ECO:0000250|UniProtKB:P04585, ECO:0000250|UniProtKB:P12497}.; FUNCTION: [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 in gRNA dimerization, packaging, tRNA incorporation and virion assembly. {ECO:0000250|UniProtKB:P04585}.; FUNCTION: [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. Also mediates cleavage of host YTHDF3. Mediates cleavage of host CARD8, thereby activating the CARD8 inflammasome, leading to the clearance of latent HIV-1 in patient CD4(+) T-cells after viral reactivation; in contrast, HIV-1 can evade CARD8-sensing when its protease remains inactive in infected cells prior to viral budding (By similarity). {ECO:0000250|UniProtKB:P04585, ECO:0000255|PROSITE-ProRule:PRU00275}.; FUNCTION: [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. {ECO:0000250|UniProtKB:P04585}.; FUNCTION: [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. {ECO:0000250|UniProtKB:P04585}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (1); Chain (10); Compositional bias (1); DNA binding (1); Domain (4); Initiator methionine (1); Lipidation (1); Metal binding (14); Modified residue (1); Motif (3); Peptide (2); Region (12); Site (12); Zinc finger (3) |
| Keywords | AIDS;Activation of host caspases by virus;Aspartyl protease;Capsid protein;DNA integration;DNA recombination;DNA-binding;DNA-directed DNA polymerase;Endonuclease;Eukaryotic host gene expression shutoff by virus;Eukaryotic host translation shutoff by virus;Host cell membrane;Host cytoplasm;Host endosome;Host gene expression shutoff by virus;Host membrane;Host nucleus;Host-virus interaction;Hydrolase;Lipid-binding;Lipoprotein;Magnesium;Membrane;Metal-binding;Modulation of host cell apoptosis by virus;Multifunctional enzyme;Myristate;Nuclease;Nucleotidyltransferase;Phosphoprotein;Protease;RNA-binding;RNA-directed DNA polymerase;Repeat;Ribosomal frameshifting;Transferase;Viral genome integration;Viral nucleoprotein;Viral penetration into host nucleus;Viral release from host cell;Virion;Virion maturation;Virus entry into host cell;Zinc;Zinc-finger |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Gag-Pol polyprotein]: Host cell membrane; Lipid-anchor. Host endosome, host multivesicular body. Note=These locations are linked to virus assembly sites. The main location is the cell membrane, but under some circumstances, late endosomal compartments can serve as productive sites for virion assembly. {ECO:0000250|UniProtKB:P12497}.; SUBCELLULAR LOCATION: [Matrix protein p17]: Virion membrane; Lipid-anchor {ECO:0000305}. Host nucleus {ECO:0000250}. Host cytoplasm {ECO:0000250}.; SUBCELLULAR LOCATION: [Capsid protein p24]: Virion {ECO:0000305}.; SUBCELLULAR LOCATION: [Nucleocapsid protein p7]: Virion {ECO:0000305}.; SUBCELLULAR LOCATION: [Reverse transcriptase/ribonuclease H]: Virion {ECO:0000305}.; SUBCELLULAR LOCATION: [Integrase]: Virion {ECO:0000305}. Host nucleus {ECO:0000305}. Host cytoplasm {ECO:0000305}. Note=Nuclear at initial phase, cytoplasmic at assembly. {ECO:0000305}. |
| Modified Residue | MOD_RES 132; /note=Phosphotyrosine; by host; /evidence=ECO:0000250 |
| Post Translational Modification | PTM: [Gag-Pol polyprotein]: Specific enzymatic cleavages by the viral protease yield mature proteins. The protease is released by autocatalytic cleavage. The polyprotein is cleaved during and after budding, this process is termed maturation. Proteolytic cleavage of p66 RT removes the RNase H domain to yield the p51 RT subunit. Nucleocapsid protein p7 might be further cleaved after virus entry. {ECO:0000250|UniProtKB:P04585, ECO:0000255|PROSITE-ProRule:PRU00405}.; PTM: [Matrix protein p17]: Tyrosine phosphorylated presumably in the virion by a host kinase. Phosphorylation is apparently not a major regulator of membrane association. {ECO:0000250|UniProtKB:P04585}.; PTM: [Capsid protein p24]: Phosphorylated possibly by host MAPK1; this phosphorylation is necessary for Pin1-mediated virion uncoating. {ECO:0000250|UniProtKB:P12493}.; PTM: [Nucleocapsid protein p7]: Methylated by host PRMT6, impairing its function by reducing RNA annealing and the initiation of reverse transcription. {ECO:0000250|UniProtKB:P03347}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | - |
| Motif | MOTIF 16..22; /note=Nuclear export signal; /evidence=ECO:0000250; MOTIF 26..32; /note=Nuclear localization signal; /evidence=ECO:0000250; MOTIF 983..999; /note=Tryptophan repeat motif; /evidence=ECO:0000250 |
| Gene Encoded By | |
| Mass | 161,650 |
| Kinetics | |
| Metal Binding | METAL 695; /note=Magnesium 1; catalytic; for reverse transcriptase activity; /evidence=ECO:0000250; METAL 770; /note=Magnesium 1; catalytic; for reverse transcriptase activity; /evidence=ECO:0000250; METAL 771; /note=Magnesium 1; catalytic; for reverse transcriptase activity; /evidence=ECO:0000250; METAL 1028; /note=Magnesium 2; catalytic; for RNase H activity; /evidence=ECO:0000250; METAL 1063; /note=Magnesium 2; catalytic; for RNase H activity; /evidence=ECO:0000250; METAL 1083; /note=Magnesium 2; catalytic; for RNase H activity; /evidence=ECO:0000250; METAL 1134; /note=Magnesium 2; catalytic; for RNase H activity; /evidence=ECO:0000250; METAL 1157; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU00450; METAL 1161; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU00450; METAL 1185; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU00450; METAL 1188; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU00450; METAL 1209; /note=Magnesium 3; catalytic; for integrase activity; /evidence=ECO:0000250; METAL 1261; /note=Magnesium 3; catalytic; for integrase activity; /evidence=ECO:0000250; METAL 1297; /note=Magnesium 3; catalytic; for integrase activity; /evidence=ECO:0000250|UniProtKB:P04585 |
| Rhea ID | RHEA:22508 |
| Cross Reference Brenda |