Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.

Apoptosis Cell Line, Tumor Gene Expression Regulation, Neoplastic Humans Intracellular Signaling Peptides and Proteins / chemistry Multiple Myeloma / genetics Proteasome Endopeptidase Complex / metabolism Transcription Factors / metabolism Transcriptional Activation Ubiquitin / metabolism Ubiquitination

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
16 12 2021
Historique:
received: 05 07 2021
accepted: 29 11 2021
entrez: 17 12 2021
pubmed: 18 12 2021
medline: 30 12 2021
Statut: epublish

Résumé

Proteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru β-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13

Identifiants

DOI: 10.1038/s41467-021-27570-4 PMID: 34916494 PMC: PMC8677766
pubmed: 34916494
doi: 10.1038/s41467-021-27570-4
pii: 10.1038/s41467-021-27570-4
pmc: PMC8677766
doi:

Substances chimiques

ADRM1 protein, human 0
Intracellular Signaling Peptides and Proteins 0
Transcription Factors 0
Ubiquitin 0
Proteasome Endopeptidase Complex EC 3.4.25.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

7318

Subventions

Organisme : Intramural NIH HHS
ID : ZIA BC011490
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011627
Pays : United States

Informations de copyright

© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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Auteurs

Xiuxiu Lu (X)

Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
ORCID: 0000-0002-9591-7334

Venkata R Sabbasani (VR)

Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
ORCID: 0000-0002-4558-2812

Vasty Osei-Amponsa (V)

Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.

Christine N Evans (CN)

Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Julianna C King (JC)

Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Sergey G Tarasov (SG)

Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.

Marzena Dyba (M)

Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.

Sudipto Das (S)

Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA.

King C Chan (KC)

Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA.

Charles D Schwieters (CD)

Computational Biomolecular Magnetic Resonance Core, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-5620, USA.
ORCID: 0000-0002-4216-4658

Sulbha Choudhari (S)

Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.

Caroline Fromont (C)

Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.

Yongmei Zhao (Y)

Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.
ORCID: 0000-0003-0800-4658

Bao Tran (B)

Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA.

Xiang Chen (X)

Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
ORCID: 0000-0002-0036-0212

Hiroshi Matsuo (H)

Basic Science Program, Center for Structural Biology, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
ORCID: 0000-0002-4559-6157

Thorkell Andresson (T)

Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD, 21702, USA.

Raj Chari (R)

Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.

Rolf E Swenson (RE)

Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Nadya I Tarasova (NI)

Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
ORCID: 0000-0002-4949-0069

Kylie J Walters (KJ)

Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA. kylie.walters@nih.gov.
ORCID: 0000-0001-7590-2891

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Proteasome endopeptidase complex › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Activation de la transcription › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Ubiquitines › Ubiquitine › Structure-guided bifunctional molecules hit a...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › Ubiquitination › Structure-guided bifunctional molecules hit a...