9eqk: Difference between revisions

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~~'''Unreleased structure'''~~

~~The entry~~ 9eqk is ~~ON HOLD~~

==WWP1 WW2-2,3-linker-WW3-WW4-HECT (WWP1-2L34H) with ordered WW2 domain==

== Structural highlights ==

<table><tr><td colspan='2'>[[9eqk]] is a 2 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=9EQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9EQK 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]] 3Å</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=9eqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9eqk OCA], [https://pdbe.org/9eqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9eqk RCSB], [https://www.ebi.ac.uk/pdbsum/9eqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9eqk ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/WWP1_HUMAN WWP1_HUMAN] 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. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF.<ref>PMID:15359284</ref> <ref>PMID:15221015</ref> <ref>PMID:12535537</ref>

== Publication Abstract from PubMed ==

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC(50) of 158.3 microM (95% CI = 128.7, 195.1 microM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC(50) of 32.7 microM (95% CI = 24.6, 44.3 microM) for WWP1 and 269.2 microM (95% CI = 209.4, 347.9 microM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a pi-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

~~Authors:~~ Dudey, A.P., ~~Hemmings, A~~.M.

Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.,Dudey AP, Rigby JM, Hughes GR, Stephenson GR, Storr TE, Chantry A, Hemmings AM J Enzyme Inhib Med Chem. 2024 Dec;39(1):2394895. doi: , 10.1080/14756366.2024.2394895. Epub 2024 Sep 2. PMID:39223706<ref>PMID:39223706</ref>

~~Description: WWP1 WW2-2~~,3-~~linker~~-~~WW3-WW4-HECT (WWP1-2L34H) with ordered WW2 domain~~

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

[[Category: ~~Unreleased~~ Structures]]

</div>

[[Category: Dudey~~, A.P~~]]

[[Category: Hemmings~~, A.M~~]]

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Dudey AP]]

[[Category: Hemmings AM]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9eqk is ON HOLD
+==WWP1 WW2-2,3-linker-WW3-WW4-HECT (WWP1-2L34H) with ordered WW2 domain==
+<StructureSection load='9eqk' size='340' side='right'caption='[[9eqk]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9eqk]] is a 2 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=9EQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9EQK 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]] 3&#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=9eqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9eqk OCA], [https://pdbe.org/9eqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9eqk RCSB], [https://www.ebi.ac.uk/pdbsum/9eqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9eqk ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/WWP1_HUMAN WWP1_HUMAN] 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. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF.<ref>PMID:15359284</ref> <ref>PMID:15221015</ref> <ref>PMID:12535537</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC(50) of 158.3 microM (95% CI = 128.7, 195.1 microM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC(50) of 32.7 microM (95% CI = 24.6, 44.3 microM) for WWP1 and 269.2 microM (95% CI = 209.4, 347.9 microM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a pi-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.
-Authors: Dudey, A.P., Hemmings, A.M.
+Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.,Dudey AP, Rigby JM, Hughes GR, Stephenson GR, Storr TE, Chantry A, Hemmings AM J Enzyme Inhib Med Chem. 2024 Dec;39(1):2394895. doi: , 10.1080/14756366.2024.2394895. Epub 2024 Sep 2. PMID:39223706<ref>PMID:39223706</ref>
-Description: WWP1 WW2-2,3-linker-WW3-WW4-HECT (WWP1-2L34H) with ordered WW2 domain
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Dudey, A.P]]
+<div class="pdbe-citations 9eqk" style="background-color:#fffaf0;"></div>
-[[Category: Hemmings, A.M]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Dudey AP]]
+[[Category: Hemmings AM]]