7qpb

From Proteopedia

(Difference between revisions)

Revision as of 06:50, 27 September 2023

Catalytic C-lobe of the HECT-type ubiquitin ligase E6AP in complex with a hybrid foldamer-peptide macrocycle

Structural highlights

7qpb is a 6 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.342Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

UBE3A_HUMAN Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM: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.^[1] ^[2]

Function

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.^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Expanding the chemical diversity of peptide macrocycle libraries for display selection is desirable to improve their potential at binding biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A helical aromatic foldamer was identified that undergoes flexizyme-mediated tRNA acylation and is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer-peptide hybrids. A hybrid macrocyle 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 Sep 14:e202308408. doi: 10.1002/anie.202308408. PMID:37707879^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jager D, Jager E, Knuth A, Chen YT, Old LJ. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int J Cancer. 1999 Nov 12;83(4):456-64. PMID:10508479
↑ Malzac P, Webber H, Moncla A, Graham JM, Kukolich M, Williams C, Pagon RA, Ramsdell LA, Kishino T, Wagstaff J. Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet. 1998 Jun;62(6):1353-60. PMID:9585605 doi:S0002-9297(07)62776-1
↑ Kumar S, Talis AL, Howley PM. Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem. 1999 Jun 25;274(26):18785-92. PMID:10373495
↑ Louria-Hayon I, Alsheich-Bartok O, Levav-Cohen Y, Silberman I, Berger M, Grossman T, Matentzoglu K, Jiang YH, Muller S, Scheffner M, Haupt S, Haupt Y. E6AP promotes the degradation of the PML tumor suppressor. Cell Death Differ. 2009 Aug;16(8):1156-66. Epub 2009 Mar 27. PMID:19325566 doi:cdd200931
↑ Mishra A, Godavarthi SK, Maheshwari M, Goswami A, Jana NR. The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. J Biol Chem. 2009 Apr 17;284(16):10537-45. Epub 2009 Feb 20. PMID:19233847 doi:M806804200
↑ Shimoji T, Murakami K, Sugiyama Y, Matsuda M, Inubushi S, Nasu J, Shirakura M, Suzuki T, Wakita T, Kishino T, Hotta H, Miyamura T, Shoji I. Identification of annexin A1 as a novel substrate for E6AP-mediated ubiquitylation. J Cell Biochem. 2009 Apr 15;106(6):1123-35. PMID:19204938 doi:10.1002/jcb.22096
↑ Mishra A, Godavarthi SK, Jana NR. UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis. 2009 Oct;36(1):26-34. Epub 2009 Jul 8. PMID:19591933 doi:S0969-9961(09)00159-4
↑ Martinez-Noel G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, Howley PM. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol. 2012 Aug;32(15):3095-106. doi: 10.1128/MCB.00201-12. Epub 2012 May, 29. PMID:22645313 doi:10.1128/MCB.00201-12
↑ Dengler S, Howard RT, Morozov V, Tsiamantas C, Huang WE, Liu Z, Dobrzanski C, Pophristic V, Brameyer S, Douat C, Suga H, Huc I. Display Selection of a Hybrid Foldamer-Peptide Macrocycle. Angew Chem Int Ed Engl. 2023 Sep 14:e202308408. PMID:37707879 doi:10.1002/anie.202308408

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7qpb"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7qpb is ON HOLD
+==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=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 at binding biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A helical aromatic foldamer was identified that undergoes flexizyme-mediated tRNA acylation and is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer-peptide hybrids. A hybrid macrocyle 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.
-Authors: Dengler, S., Howard, R.T., Morozov, V., Tsiamantas, C., Douat, C., Suga, H., Huc, I.
+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 Sep 14:e202308408. doi: 10.1002/anie.202308408. PMID:37707879<ref>PMID:37707879</ref>
-Description: Catalytic C-lobe of the HECT-type ubiquitin ligase E6AP in complex with a hybrid foldamer-peptide macrocycle
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Suga, H]]
+<div class="pdbe-citations 7qpb" style="background-color:#fffaf0;"></div>
-[[Category: Douat, C]]
+== References ==
-[[Category: Morozov, V]]
+<references/>
-[[Category: Tsiamantas, C]]
+__TOC__
-[[Category: Dengler, S]]
+</StructureSection>
-[[Category: Huc, I]]
+[[Category: Homo sapiens]]
-[[Category: Howard, R.T]]
+[[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]]

7qpb

From Proteopedia

Revision as of 06:50, 27 September 2023

Catalytic C-lobe of the HECT-type ubiquitin ligase E6AP in complex with a hybrid foldamer-peptide macrocycle

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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