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| <SX load='6nil' size='340' side='right' viewer='molstar' caption='[[6nil]], [[Resolution|resolution]] 3.90Å' scene=''> | | <SX load='6nil' size='340' side='right' viewer='molstar' caption='[[6nil]], [[Resolution|resolution]] 3.90Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6nil]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Hiv-1 Hiv-1] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NIL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6NIL FirstGlance]. <br> | | <table><tr><td colspan='2'>[[6nil]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NIL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NIL FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.9Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APOBEC3F ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CBFB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), vif ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11698 HIV-1])</td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Single-stranded_DNA_cytosine_deaminase Single-stranded DNA cytosine deaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.38 3.5.4.38] </span></td></tr>
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6nil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nil OCA], [https://pdbe.org/6nil PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nil RCSB], [https://www.ebi.ac.uk/pdbsum/6nil PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nil ProSAT]</span></td></tr> |
| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6nil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nil OCA], [http://pdbe.org/6nil PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nil RCSB], [http://www.ebi.ac.uk/pdbsum/6nil PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nil ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Disease ==
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| [[http://www.uniprot.org/uniprot/PEBB_HUMAN PEBB_HUMAN]] Note=A chromosomal aberration involving CBFB is associated with acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein that consists of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11.
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| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/ABC3F_HUMAN ABC3F_HUMAN]] DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits antiviral activity against vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity also against hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV) and may inhibit the mobility of LTR and non-LTR retrotransposons. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.<ref>PMID:15152192</ref> <ref>PMID:16527742</ref> <ref>PMID:16378963</ref> <ref>PMID:19458006</ref> <ref>PMID:20219927</ref> <ref>PMID:20335265</ref> <ref>PMID:20062055</ref> <ref>PMID:21496894</ref> <ref>PMID:21835787</ref> <ref>PMID:22915799</ref> <ref>PMID:22807680</ref> <ref>PMID:23097438</ref> <ref>PMID:23152537</ref> [[http://www.uniprot.org/uniprot/VIF_HV1N5 VIF_HV1N5]] Counteracts the innate antiviral activity of human APOBEC3F and APOBEC3G. Forms a complex with host APOBEC3F and APOBEC3G thus preventing the entry of these lethally hypermutating enzymes into progeny virions. Recruits an active E3 ubiquitin ligase complex composed of elongin BC, CUL5, and RBX2 to induce polyubiquitination of APOBEC3G and APOBEC3F. In turn, they are directed to the 26S proteasome for degradation. Vif interaction with APOBEC3G also blocks its cytidine deaminase activity in a proteasome-independent manner, suggesting a dual inhibitory mechanism. May interact directly with APOBEC3G mRNA in order to inhibit its translation. Seems to play a role in viral morphology by affecting the stability of the viral nucleoprotein core. Finally, Vif also contributes to the G2 cell cycle arrest observed in HIV infected cells (By similarity).<ref>PMID:8184544</ref> <ref>PMID:14557625</ref> [[http://www.uniprot.org/uniprot/PEBB_HUMAN PEBB_HUMAN]] CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. CBFB enhances DNA binding by RUNX1. | | [https://www.uniprot.org/uniprot/VIF_HV1N5 VIF_HV1N5] Counteracts the innate antiviral activity of human APOBEC3F and APOBEC3G. Forms a complex with host APOBEC3F and APOBEC3G thus preventing the entry of these lethally hypermutating enzymes into progeny virions. Recruits an active E3 ubiquitin ligase complex composed of elongin BC, CUL5, and RBX2 to induce polyubiquitination of APOBEC3G and APOBEC3F. In turn, they are directed to the 26S proteasome for degradation. Vif interaction with APOBEC3G also blocks its cytidine deaminase activity in a proteasome-independent manner, suggesting a dual inhibitory mechanism. May interact directly with APOBEC3G mRNA in order to inhibit its translation. Seems to play a role in viral morphology by affecting the stability of the viral nucleoprotein core. Finally, Vif also contributes to the G2 cell cycle arrest observed in HIV infected cells (By similarity).<ref>PMID:8184544</ref> <ref>PMID:14557625</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of human immunodeficiency virus type 1 (HIV-1) replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and the cellular cofactor core-binding factor beta (CBFbeta) at 3.9-A resolution. The structure shows that Vif and CBFbeta form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFbeta beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F.
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| Structural basis of antagonism of human APOBEC3F by HIV-1 Vif.,Hu Y, Desimmie BA, Nguyen HC, Ziegler SJ, Cheng TC, Chen J, Wang J, Wang H, Zhang K, Pathak VK, Xiong Y Nat Struct Mol Biol. 2019 Dec;26(12):1176-1183. doi: 10.1038/s41594-019-0343-6., Epub 2019 Dec 2. PMID:31792451<ref>PMID:31792451</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 6nil" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| | *[[Core-binding factor|Core-binding factor]] |
| *[[Virion infectivity factor|Virion infectivity factor]] | | *[[Virion infectivity factor|Virion infectivity factor]] |
| == References == | | == References == |
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| __TOC__ | | __TOC__ |
| </SX> | | </SX> |
| [[Category: Hiv-1]] | | [[Category: Homo sapiens]] |
| [[Category: Human]] | | [[Category: Human immunodeficiency virus 1]] |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Single-stranded DNA cytosine deaminase]]
| | [[Category: Hu Y]] |
| [[Category: Hu, Y]] | | [[Category: Xiong Y]] |
| [[Category: Xiong, Y]] | |
| [[Category: Antiviral protein]]
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| [[Category: Hiv viral protein]]
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| [[Category: Human antiviral restriction factor]]
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