View source for 9on8


==Immature HIV-1 CACTD-SP1 lattice with Maturation inhibitor PF-46396 (R) and Inositol hexakisphosphate (IP6)==
<StructureSection load='9on8' size='340' side='right'caption='[[9on8]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9on8]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_(NEW_YORK-5_ISOLATE) Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9ON8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9ON8 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solid-state NMR, 10 models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CCY:1-{(2R)-2-(4-tert-butylphenyl)-2-[(2,3-dihydro-1H-inden-2-yl)amino]ethyl}-3-(trifluoromethyl)pyridin-2(1H)-one'>A1CCY</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene></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=9on8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9on8 OCA], [https://pdbe.org/9on8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9on8 RCSB], [https://www.ebi.ac.uk/pdbsum/9on8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9on8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/POL_HV1N5 POL_HV1N5] 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 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. The second function is to play a role in nuclear localization of the viral genome at the very start of cell infection. Matrix protein is the part of the pre-integration complex. It binds in the cytoplasm the human BAF protein which prevent autointegration of the viral genome, and might be included in virions at the ration of zero to 3 BAF dimer per virion. The myristoylation signal and the NLS thus exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (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. Interaction with human PPIA/CYPA protects the virus from restriction by human TRIM5-alpha and from an unknown antiviral activity in human cells. This capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species (By similarity).  Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).  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 (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 (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Among the different types of HIV-1 maturation inhibitors, those that stabilize the junction between the capsid protein C-terminal domain (CA(CTD)) and the spacer peptide 1 (SP1) within the immature Gag lattice are promising candidates for antiretroviral therapies. Here, we report the atomic-resolution structure of CA(CTD)-SP1 assemblies with the small-molecule maturation inhibitor PF-46396 and the assembly cofactor inositol hexakisphosphate (IP6), determined by magic angle spinning (MAS) NMR spectroscopy. Our results reveal that although the two PF-46396 enantiomers exhibit distinct binding modes, they both possess similar anti-HIV potency. PF-46396 binding arrests IP6 dynamics in the six-helix bundle pore, and the two enantiomers induce unique IP6 orientations in the pore. Importantly, our data suggest the presence of monoanionic IP6 form in the complex. Our study establishes the structural basis for PF-46396 action and suggests a mechanistic model for drug resistance.

Structural Basis for HIV-1 Maturation Inhibition by PF-46396 Determined by MAS NMR.,Zadorozhnyi R, Quinn CM, Zadrozny KK, Ablan SD, Kennedy BJ, Yap GPA, Sanner D, Kraml C, Freed EO, Ganser-Pornillos BK, Pornillos O, Gronenborn AM, Polenova T J Am Chem Soc. 2025 Sep 24;147(38):34487-34497. doi: 10.1021/jacs.5c08455. Epub , 2025 Sep 9. PMID:40924873<ref>PMID:40924873</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9on8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Ablan SD]]
[[Category: Freed EO]]
[[Category: Ganser-Pornillos BK]]
[[Category: Gronenborn AM]]
[[Category: Kennedy BJ]]
[[Category: Kraml C]]
[[Category: Polenova T]]
[[Category: Pornillos O]]
[[Category: Quinn CM]]
[[Category: Sanner D]]
[[Category: Yap GPA]]
[[Category: Zadorozhnyi R]]
[[Category: Zadrozny KK]]