View source for 5hpl


==System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes: Rsp5 and UbV R5.4==
<StructureSection load='5hpl' size='340' side='right'caption='[[5hpl]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hpl]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HPL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HPL 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]] 2.31&#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=5hpl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hpl OCA], [https://pdbe.org/5hpl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hpl RCSB], [https://www.ebi.ac.uk/pdbsum/5hpl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hpl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RSP5_YEAST RSP5_YEAST] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Component of a RSP5 ubiquitin ligase complex which specifies polyubiquitination and intracellular trafficking of the general amino acid permease GAP1 as well as other cell surface proteins like GAP1, FUR4, MAL61, PMA1 and STE2. The RSP5-BUL1/2 complex is also necessary for the heat-shock element (HSE)-mediated gene expression, nitrogen starvation GLN3-dependent transcription, pressure-induced differential regulation of the two tryptophan permeases TAT1 and TAT2 and sorting efficiency into multivesicular bodies. Also acts on RBP1. Plays a role in tolerance to o-dinitrobenzene. Involved in actin cytoskeleton organization and dynamics. Ubiquitinates the LAS17-binding proteins LSB1 and PIN3/LSB2 without directing them for degradation and affects LAS17 levels in a SLA1-dependent and LSB1/2-independent manner.<ref>PMID:7708685</ref> <ref>PMID:9931424</ref> <ref>PMID:9858558</ref> <ref>PMID:12163175</ref> <ref>PMID:12821147</ref> <ref>PMID:14560004</ref> <ref>PMID:15247235</ref> <ref>PMID:15020711</ref> <ref>PMID:15933713</ref> <ref>PMID:16864574</ref> <ref>PMID:17079730</ref> <ref>PMID:22000681</ref> 
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== Publication Abstract from PubMed ==
HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.

System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.,Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS Mol Cell. 2016 Apr 7;62(1):121-36. doi: 10.1016/j.molcel.2016.02.005. Epub 2016, Mar 3. PMID:26949039<ref>PMID:26949039</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 5hpl" 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: Saccharomyces cerevisiae]]
[[Category: Kamadurai HB]]
[[Category: Schulman BA]]
[[Category: Wu K-P]]