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<StructureSection load='1gh6' size='340' side='right'caption='[[1gh6]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
<StructureSection load='1gh6' size='340' side='right'caption='[[1gh6]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1gh6]] is a 2 chain structure. The November 2003 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Simian Virus 40''  by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2003_11 10.2210/rcsb_pdb/mom_2003_11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GH6 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1gh6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Macaca_mulatta_polyomavirus_1 Macaca mulatta polyomavirus 1]. The November 2003 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Simian Virus 40''  by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2003_11 10.2210/rcsb_pdb/mom_2003_11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GH6 FirstGlance]. <br>
</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=1gh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gh6 OCA], [https://pdbe.org/1gh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gh6 RCSB], [https://www.ebi.ac.uk/pdbsum/1gh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gh6 ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</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=1gh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gh6 OCA], [https://pdbe.org/1gh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gh6 RCSB], [https://www.ebi.ac.uk/pdbsum/1gh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gh6 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/RB_HUMAN RB_HUMAN]] Defects in RB1 are the cause of childhood cancer retinoblastoma (RB) [MIM:[https://omim.org/entry/180200 180200]]. RB is a congenital malignant tumor that arises from the nuclear layers of the retina. It occurs in about 1:20'000 live births and represents about 2% of childhood malignancies. It is bilateral in about 30% of cases. Although most RB appear sporadically, about 20% are transmitted as an autosomal dominant trait with incomplete penetrance. The diagnosis is usually made before the age of 2 years when strabismus or a gray to yellow reflex from pupil ('cat eye') is investigated.<ref>PMID:2594029</ref> <ref>PMID:1352883</ref> <ref>PMID:8346255</ref> <ref>PMID:7704558</ref> <ref>PMID:7927327</ref> <ref>PMID:8605116</ref> <ref>PMID:7795591</ref> <ref>PMID:8776589</ref> <ref>PMID:9311732</ref> <ref>PMID:9140452</ref> <ref>PMID:10671068</ref> <ref>PMID:9973307</ref> <ref>PMID:11524739</ref>  Defects in RB1 are a cause of susceptibility to bladder cancer (BLC) [MIM:[https://omim.org/entry/109800 109800]]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences.  Defects in RB1 are a cause of osteogenic sarcoma (OSRC) [MIM:[https://omim.org/entry/259500 259500]].
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/LT_SV40 LT_SV40]] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.<ref>PMID:8647434</ref> <ref>PMID:9632777</ref> <ref>PMID:9488456</ref> <ref>PMID:15680424</ref> <ref>PMID:15611062</ref> <ref>PMID:17341466</ref> <ref>PMID:18922873</ref>  Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.<ref>PMID:8647434</ref> <ref>PMID:9632777</ref> <ref>PMID:9488456</ref> <ref>PMID:15680424</ref> <ref>PMID:15611062</ref> <ref>PMID:17341466</ref> <ref>PMID:18922873</ref> [[https://www.uniprot.org/uniprot/RB_HUMAN RB_HUMAN]] Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, SUV420H1 and SUV420H2, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity). In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.<ref>PMID:15084261</ref> 
[https://www.uniprot.org/uniprot/LT_SV40 LT_SV40] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.<ref>PMID:8647434</ref> <ref>PMID:9632777</ref> <ref>PMID:9488456</ref> <ref>PMID:15680424</ref> <ref>PMID:15611062</ref> <ref>PMID:17341466</ref> <ref>PMID:18922873</ref>  Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.<ref>PMID:8647434</ref> <ref>PMID:9632777</ref> <ref>PMID:9488456</ref> <ref>PMID:15680424</ref> <ref>PMID:15611062</ref> <ref>PMID:17341466</ref> <ref>PMID:18922873</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Macaca mulatta polyomavirus 1]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: Simian Virus 40]]
[[Category: Simian Virus 40]]
[[Category: Cho, Y]]
[[Category: Cho Y]]
[[Category: Kim, H Y]]
[[Category: Kim HY]]
[[Category: Antitumor protein]]
[[Category: Oncoprotein]]
[[Category: Tumor suppressor]]

Latest revision as of 06:11, 9 August 2023

RETINOBLASTOMA POCKET COMPLEXED WITH SV40 LARGE T ANTIGEN

1gh6, resolution 3.20Å

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