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==Cryo-EM structure of a double loaded human UBA7-UBE2L6-ISG15 thioester mimetic complex (Form 1)==
<StructureSection load='8sea' size='340' side='right'caption='[[8sea]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8sea]] is a 4 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=8SEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SEA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</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=8sea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sea OCA], [https://pdbe.org/8sea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sea RCSB], [https://www.ebi.ac.uk/pdbsum/8sea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sea ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/UBA7_HUMAN UBA7_HUMAN] E1-activating enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of ISG15 to additional interferon stimulated proteins (ISGs) as well as other cellular proteins such as P53 in a process termed protein ISGylation (PubMed:27545325). Plays an essential role in antiviral immunity together with ISG15 by restricting the replication of many viruses including rabies virus, influenza virus, sindbis virus, rotavirus or human cytomegalovirus (PubMed:16254333, PubMed:19073728, PubMed:29056542, PubMed:29743376, PubMed:37722521). For example, ISG15 modification of influenza A protein NS1 disrupts the association of the NS1 with importin-alpha leading to NS1 nuclear import inhibition (PubMed:20133869). ISGylation of human cytomegalovirs protein UL26 regulates its stability and inhibits its activities to suppress NF-kappa-B signaling (PubMed:27564865).<ref>PMID:16254333</ref> <ref>PMID:19073728</ref> <ref>PMID:20133869</ref> <ref>PMID:27545325</ref> <ref>PMID:27564865</ref> <ref>PMID:29056542</ref> <ref>PMID:29743376</ref> <ref>PMID:37722521</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
ISG15 plays a crucial role in the innate immune response and has been well-studied due to its antiviral activity and regulation of signal transduction, apoptosis, and autophagy. ISG15 is a ubiquitin-like protein that is activated by an E1 enzyme (Uba7) and transferred to a cognate E2 enzyme (UBE2L6) to form a UBE2L6-ISG15 intermediate that functions with E3 ligases that catalyze conjugation of ISG15 to target proteins. Despite its biological importance, the molecular basis by which Uba7 catalyzes ISG15 activation and transfer to UBE2L6 is unknown as there is no available structure of Uba7. Here, we present cryo-EM structures of human Uba7 in complex with UBE2L6, ISG15 adenylate, and ISG15 thioester intermediate that are poised for catalysis of Uba7-UBE2L6-ISG15 thioester transfer. Our structures reveal a unique overall architecture of the complex compared to structures from the ubiquitin conjugation pathway, particularly with respect to the location of ISG15 thioester intermediate. Our structures also illuminate the molecular basis for Uba7 activities and for its exquisite specificity for ISG15 and UBE2L6. Altogether, our structural, biochemical, and human cell-based data provide significant insights into the functions of Uba7, UBE2L6, and ISG15 in cells.

Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer.,Afsar M, Liu G, Jia L, Ruben EA, Nayak D, Sayyad Z, Bury PDS, Cano KE, Nayak A, Zhao XR, Shukla A, Sung P, Wasmuth EV, Gack MU, Olsen SK Nat Commun. 2023 Aug 8;14(1):4786. doi: 10.1038/s41467-023-39780-z. PMID:37553340<ref>PMID:37553340</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8sea" style="background-color:#fffaf0;"></div>

==See Also==
*[[3D structures of Ubiquitin activating enzyme|3D structures of Ubiquitin activating enzyme]]
*[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Afsar M]]
[[Category: Jia L]]
[[Category: Olsen SK]]
[[Category: Ruben EA]]