View source for 7qpb


==Catalytic C-lobe of the HECT-type ubiquitin ligase E6AP in complex with a hybrid foldamer-peptide macrocycle==
<StructureSection load='7qpb' size='340' side='right'caption='[[7qpb]], [[Resolution|resolution]] 2.34&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7qpb]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QPB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QPB 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]] 2.342&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9JC:4-(aminomethyl)-8-azanyl-quinoline-2-carbaldehyde'>9JC</scene>, <scene name='pdbligand=9JV:8-azanyl-4-methoxy-quinoline-2-carboxylic+acid'>9JV</scene>, <scene name='pdbligand=CCS:CARBOXYMETHYLATED+CYSTEINE'>CCS</scene>, <scene name='pdbligand=GM1:AMINOMETHYLAMIDE'>GM1</scene>, <scene name='pdbligand=ZY9:6-(aminomethyl)pyridine-2-carboxylic+acid'>ZY9</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=7qpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qpb OCA], [https://pdbe.org/7qpb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qpb RCSB], [https://www.ebi.ac.uk/pdbsum/7qpb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qpb 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/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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Expanding the chemical diversity of peptide macrocycle libraries for display selection is desirable to improve their potential to bind biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A foldamer was first identified that undergoes flexizyme-mediated tRNA acylation and that is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer-peptide hybrids. A hybrid macrocyclic nanomolar binder to the C-lobe of the E6AP HECT domain was selected that showed a highly converged peptide sequence. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions with the target protein. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. These results altogether represent a significant extension of the chemical space amenable to display selection and highlight possible benefits of inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition.

Display Selection of a Hybrid Foldamer-Peptide Macrocycle.,Dengler S, Howard RT, Morozov V, Tsiamantas C, Huang WE, Liu Z, Dobrzanski C, Pophristic V, Brameyer S, Douat C, Suga H, Huc I Angew Chem Int Ed Engl. 2023 Nov 13;62(46):e202308408. doi: , 10.1002/anie.202308408. Epub 2023 Oct 13. PMID:37707879<ref>PMID:37707879</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7qpb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Dengler S]]
[[Category: Douat C]]
[[Category: Howard RT]]
[[Category: Huc I]]
[[Category: Morozov V]]
[[Category: Suga H]]
[[Category: Tsiamantas C]]