8hje

From Proteopedia

(Difference between revisions)

Revision as of 07:33, 3 May 2023

Vismodegib binds to the catalytical domain of human Ubiquitin-Specific Protease 28

Structural highlights

8hje is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4]

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 Apr 11;254:115369. doi: 10.1016/j.ejmech.2023.115369. PMID:37075624^[5]

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

References

↑ Zhang D, Zaugg K, Mak TW, Elledge SJ. A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Cell. 2006 Aug 11;126(3):529-42. PMID:16901786 doi:http://dx.doi.org/10.1016/j.cell.2006.06.039
↑ Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, Moll R, Elledge SJ, Eilers M. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007 Jul;9(7):765-74. Epub 2007 Jun 10. PMID:17558397 doi:http://dx.doi.org/10.1038/ncb1601
↑ Popov N, Herold S, Llamazares M, Schulein C, Eilers M. Fbw7 and Usp28 regulate myc protein stability in response to DNA damage. Cell Cycle. 2007 Oct 1;6(19):2327-31. Epub 2007 Jul 26. PMID:17873522
↑ Bassermann F, Frescas D, Guardavaccaro D, Busino L, Peschiaroli A, Pagano M. The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell. 2008 Jul 25;134(2):256-67. doi: 10.1016/j.cell.2008.05.043. PMID:18662541 doi:http://dx.doi.org/10.1016/j.cell.2008.05.043
↑ 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. Structure-based discovery of potent USP28 inhibitors derived from Vismodegib. Eur J Med Chem. 2023 Apr 11;254:115369. PMID:37075624 doi:10.1016/j.ejmech.2023.115369

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8hje"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8hje is ON HOLD  until Paper Publication
+==Vismodegib binds to the catalytical domain of human Ubiquitin-Specific Protease 28==
+<StructureSection load='8hje' size='340' side='right'caption='[[8hje]], [[Resolution|resolution]] 2.85&Aring;' 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='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.
-Authors: Shi, L., Wang, H., Xu, Z., Xiong, B., Zhang, N.
+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 Apr 11;254:115369. doi: 10.1016/j.ejmech.2023.115369. PMID:37075624<ref>PMID:37075624</ref>
-Description: Vismodegib binds to the catalytical domain of human Ubiquitin-Specific Protease 28
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhang, N]]
+<div class="pdbe-citations 8hje" style="background-color:#fffaf0;"></div>
-[[Category: Xiong, B]]
+== References ==
-[[Category: Xu, Z]]
+<references/>
-[[Category: Shi, L]]
+__TOC__
-[[Category: Wang, H]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Shi L]]
+[[Category: Wang H]]
+[[Category: Xiong B]]
+[[Category: Xu Z]]
+[[Category: Zhang N]]

8hje

From Proteopedia

Revision as of 07:33, 3 May 2023

Vismodegib binds to the catalytical domain of human Ubiquitin-Specific Protease 28

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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