8hje
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 8hje is ON HOLD Authors: Shi, L., Wang, H., Xu, Z., Xiong, B., Zhang, N. Description: Vismodegib binds to the catalytical domain of human Ubiquitin...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Vismodegib binds to the catalytical domain of human Ubiquitin-Specific Protease 28== | |
| + | <StructureSection load='8hje' size='340' side='right'caption='[[8hje]], [[Resolution|resolution]] 2.85Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8hje]] is a 1 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=8HJE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HJE 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]] 2.85Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VIS:2-CHLORANYL-~{N}-(4-CHLORANYL-3-PYRIDIN-2-YL-PHENYL)-4-METHYLSULFONYL-BENZAMIDE'>VIS</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=8hje FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hje OCA], [https://pdbe.org/8hje PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hje RCSB], [https://www.ebi.ac.uk/pdbsum/8hje PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hje ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/UBP28_HUMAN UBP28_HUMAN] Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus.<ref>PMID:16901786</ref> <ref>PMID:17558397</ref> <ref>PMID:17873522</ref> <ref>PMID:18662541</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Ubiquitin-specific proteases (USPs) 28 is overexpressed in multiple types of cancers. The development of potent USP28 inhibitors is still in primitive stage. We previously reported our discovery of Vismodegib as a USP28 inhibitor by screening a commercially available drug library. Herein, we report our efforts to solve the cocrystal structure of Vismodegib bound to USP28 for the first time and subsequent structure-based optimization leading to a series of Vismodegib derivatives as potent USP28 inhibitors. Based on the cocrystal structure, elaborative SARs exploration was carried out to afford much more potent USP28 inhibitors than Vismodegib. The representative compounds 9l, 9o and 9p bearing high potency on USP28 showed high selectivity over USP2, USP7, USP8, USP9x, UCHL3 and UCHL5. The detailed cellular assay suggested that compounds 9l, 9o and 9p could cause cytotoxicity in both human colorectal cancer and lung squamous carcinoma cells and significantly enhance the sensitivity of colorectal cancer cells to Regorafenib. Further immunoblotting analysis indicated that compounds 9l, 9o and 9p could dose-dependently down-regulate the cellular level of c-Myc through ubiquitin-proteasome system and anti-cancer effects could mainly be attributed to their inhibition on USP28 but not involving the Hedgehog-Smoothened pathway. Thus, our work provided a series of novel and potent USP28 inhibitors derived from Vismodegib and may contribute to the development of USP28 inhibitors. | ||
| - | + | Structure-based discovery of potent USP28 inhibitors derived from Vismodegib.,Zhou D, Xu Z, Huang Y, Wang H, Zhu X, Zhang W, Song W, Gao T, Liu T, Wang M, Shi L, Zhang N, Xiong B Eur J Med Chem. 2023 Jun 5;254:115369. doi: 10.1016/j.ejmech.2023.115369. Epub , 2023 Apr 11. PMID:37075624<ref>PMID:37075624</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 8hje" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | |
| - | [[Category: | + | ==See Also== |
| - | [[Category: | + | *[[Thioesterase 3D structures|Thioesterase 3D structures]] |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Shi L]] | ||
| + | [[Category: Wang H]] | ||
| + | [[Category: Xiong B]] | ||
| + | [[Category: Xu Z]] | ||
| + | [[Category: Zhang N]] | ||
Current revision
Vismodegib binds to the catalytical domain of human Ubiquitin-Specific Protease 28
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Categories: Homo sapiens | Large Structures | Shi L | Wang H | Xiong B | Xu Z | Zhang N
