View source for 4xr8


==Crystal structure of the HPV16 E6/E6AP/p53 ternary complex at 2.25 A resolution==
<StructureSection load='4xr8' size='340' side='right'caption='[[4xr8]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4xr8]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_papillomavirus_type_16 Human papillomavirus type 16]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XR8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XR8 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]] 2.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4xr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xr8 OCA], [https://pdbe.org/4xr8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xr8 RCSB], [https://www.ebi.ac.uk/pdbsum/4xr8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xr8 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN] Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:[https://omim.org/entry/105830 105830]; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.<ref>PMID:10508479</ref> <ref>PMID:9585605</ref> 
== Function ==
[https://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[https://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.<ref>PMID:10373495</ref> <ref>PMID:19325566</ref> <ref>PMID:19233847</ref> <ref>PMID:19204938</ref> <ref>PMID:19591933</ref> <ref>PMID:22645313</ref> 
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== Publication Abstract from PubMed ==
The p53 pro-apoptotic tumour suppressor is mutated or functionally altered in most cancers. In epithelial tumours induced by 'high-risk' mucosal human papilloma viruses, including human cervical carcinoma and a growing number of head-and-neck cancers, p53 is degraded by the viral oncoprotein E6 (ref. 2). In this process, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP. Subsequently, the E6/E6AP heterodimer recruits and degrades p53 (ref. 4). Neither E6 nor E6AP are separately able to recruit p53 (refs 3, 5), and the precise mode of assembly of E6, E6AP and p53 is unknown. Here we solve the crystal structure of a ternary complex comprising full-length human papilloma virus type 16 (HPV-16) E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free and bound p53 molecules. The E6/E6AP/p53 complex represents a prototype of viral hijacking of both the ubiquitin-mediated protein degradation pathway and the p53 tumour suppressor pathway. The present structure provides a framework for the design of inhibitory therapeutic strategies against oncogenesis mediated by human papilloma virus.

Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53.,Martinez-Zapien D, Ruiz FX, Poirson J, Mitschler A, Ramirez J, Forster A, Cousido-Siah A, Masson M, Vande Pol S, Podjarny A, Trave G, Zanier K Nature. 2016 Jan 28;529(7587):541-5. doi: 10.1038/nature16481. Epub 2016 Jan 20. PMID:26789255<ref>PMID:26789255</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4xr8" style="background-color:#fffaf0;"></div>

==See Also==
*[[P53 3D structures|P53 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Escherichia coli K-12]]
[[Category: Homo sapiens]]
[[Category: Human papillomavirus type 16]]
[[Category: Large Structures]]
[[Category: Martinez-Zapien D]]
[[Category: Mitschler A]]
[[Category: Podjarny A]]
[[Category: Ruiz FX]]
[[Category: Trave G]]
[[Category: Zanier K]]