1n4m: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:1n4m.gif|left|200px]]<br /><applet load="1n4m" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="1n4m, resolution 2.20&Aring;" />
-'''Structure of Rb tumor suppressor bound to the transactivation domain of E2F-2'''<br />
-==Overview==
+==Structure of Rb tumor suppressor bound to the transactivation domain of E2F-2==
-Repression of E2F transcription activity by the retinoblastoma (Rb) tumor suppressor through its interaction with the transactivation domain of the E2F transcription factor is one of the central features of G1/S arrest in the mammalian cell cycle. Deregulation of the Rb-E2F interaction results in hyperproliferation, lack of differentiation, and apoptosis, and can lead to cancer. The 2.2-A crystal structure of the Rb pocket complexed with an 18-residue transactivation-domain peptide of E2F-2 reveals that the boomerang-shaped peptide binds to the highly conserved interface between the A-box and the B-box of the Rb pocket in a bipartite manner. The N-terminal segment of the E2F-2 peptide in an extended beta-strand-like structure interacts with helices from the conserved groove at the A-B interface, whereas the C-terminal segment, which contains one 3(10) helix, binds to a groove mainly formed by A-box helices. The flexibility in the middle of the E2F-2 peptide is essential for the tight association of E2F to the Rb pocket. The binding of Rb to the E2F-2 peptide conceals several conserved residues that are crucial for transcription activation of E2F. We provide the structural basis for the Rb-mediated repression of E2F transcription activity without the requirement of histone-modifying enzymes.
+<StructureSection load='1n4m' size='340' side='right'caption='[[1n4m]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1n4m]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N4M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1N4M FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#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=1n4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1n4m OCA], [https://pdbe.org/1n4m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1n4m RCSB], [https://www.ebi.ac.uk/pdbsum/1n4m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1n4m ProSAT]</span></td></tr>
+</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 ==
+[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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/n4/1n4m_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1n4m ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-N4M is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N4M OCA].
+*[[Retinoblastoma protein|Retinoblastoma protein]]
+== References ==
-==Reference==
+<references/>
-Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor., Lee C, Chang JH, Lee HS, Cho Y, Genes Dev. 2002 Dec 15;16(24):3199-212. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12502741 12502741]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Chang, J H.]]
+[[Category: Chang JH]]
-[[Category: Cho, Y.]]
+[[Category: Cho Y]]
-[[Category: Lee, C.]]
+[[Category: Lee C]]
-[[Category: Lee, H S.]]
+[[Category: Lee HS]]
-[[Category: protein-peptide complex]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:02:12 2008''