Mechanism of degrader-targeted protein ubiquitinability

Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanis...

Full description

Saved in:
Bibliographic Details
Published inScience advances Vol. 10; no. 41; p. eado6492
Main Authors Crowe, Charlotte, Nakasone, Mark A, Chandler, Sarah, Craigon, Conner, Sathe, Gajanan, Tatham, Michael H, Makukhin, Nikolai, Hay, Ronald T, Ciulli, Alessio
Format Journal Article
LanguageEnglish
Published United States 11.10.2024
Subjects
Online AccessGet full text

Cover

Loading…
Abstract Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 toward UBE2R1-ubiquitin, and Lys at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4 , with cellular degradation and ubiquitinomics confirming the importance of Lys and nearby Lys /Lys , identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.
AbstractList Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4BD2 toward UBE2R1-ubiquitin, and Lys456 at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4BD2, with cellular degradation and ubiquitinomics confirming the importance of Lys456 and nearby Lys368/Lys445, identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4BD2 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4BD2 toward UBE2R1-ubiquitin, and Lys456 at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4BD2, with cellular degradation and ubiquitinomics confirming the importance of Lys456 and nearby Lys368/Lys445, identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4BD2 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.
Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 BD2 toward UBE2R1-ubiquitin, and Lys 456 at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4 BD2 , with cellular degradation and ubiquitinomics confirming the importance of Lys 456 and nearby Lys 368 /Lys 445 , identifying the “ubiquitination zone.” Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 BD2 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design. PROTAC-targeted protein ubiquitination specificity revealed by structures with cullin RING E3 ligase and E2-ubiquitin.
Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 toward UBE2R1-ubiquitin, and Lys at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4 , with cellular degradation and ubiquitinomics confirming the importance of Lys and nearby Lys /Lys , identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.
Author Nakasone, Mark A
Hay, Ronald T
Ciulli, Alessio
Chandler, Sarah
Sathe, Gajanan
Craigon, Conner
Tatham, Michael H
Crowe, Charlotte
Makukhin, Nikolai
Author_xml – sequence: 1
  givenname: Charlotte
  orcidid: 0000-0003-2068-8255
  surname: Crowe
  fullname: Crowe, Charlotte
  organization: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee DD1 5EH, UK
– sequence: 2
  givenname: Mark A
  orcidid: 0000-0002-1362-191X
  surname: Nakasone
  fullname: Nakasone, Mark A
  organization: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee DD1 5EH, UK
– sequence: 3
  givenname: Sarah
  surname: Chandler
  fullname: Chandler, Sarah
  organization: Division of Molecular, Cellular and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
– sequence: 4
  givenname: Conner
  surname: Craigon
  fullname: Craigon, Conner
  organization: Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee DD1 5JJ, UK
– sequence: 5
  givenname: Gajanan
  orcidid: 0000-0002-6239-5365
  surname: Sathe
  fullname: Sathe, Gajanan
  organization: Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee DD1 5JJ, UK
– sequence: 6
  givenname: Michael H
  surname: Tatham
  fullname: Tatham, Michael H
  organization: Division of Molecular, Cellular and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
– sequence: 7
  givenname: Nikolai
  orcidid: 0000-0003-2465-0748
  surname: Makukhin
  fullname: Makukhin, Nikolai
  organization: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee DD1 5EH, UK
– sequence: 8
  givenname: Ronald T
  orcidid: 0000-0001-7113-9024
  surname: Hay
  fullname: Hay, Ronald T
  organization: Division of Molecular, Cellular and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
– sequence: 9
  givenname: Alessio
  orcidid: 0000-0002-8654-1670
  surname: Ciulli
  fullname: Ciulli, Alessio
  organization: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee DD1 5EH, UK
BackLink https://www.ncbi.nlm.nih.gov/pubmed/39392888$$D View this record in MEDLINE/PubMed
BookMark eNpNkLtOw0AQRVcoiISQlhK5pHHYh72PEkUEkIJooLbGu-OwyI9k10bK32OUgKhminPvjM4lmbRdi4RcM7pkjMu7aD24ryW4TmaGn5EZFypPeZ7pyb99ShYxflJKWSZlzswFmQojDNdaz4h6QfsBrY9N0lWJw20AhyHtIWyxR5fsQtejb5Oh9PvB976F0te-P1yR8wrqiIvTnJP39cPb6indvD4-r-43qeWc9qm0qMpS29LieI4KzrVk3BkAgS4TCNLoSlkLZYYCEJ0Ep5STCgSnVhkxJ7fH3vGR_YCxLxofLdY1tNgNsRCM5WosMXpEl0fUhi7GgFWxC76BcCgYLX58FUdfxcnXGLg5dQ9lg-4P_7UjvgFJTWsW
Cites_doi 10.1007/s00249-021-01513-9
10.1002/cmdc.202300464
10.1146/annurev-pharmtox-022123-104147
10.1038/nchembio.2329
10.1038/s41589-018-0055-y
10.1016/j.chembiol.2017.09.010
10.1038/s41392-022-00966-4
10.1126/science.aab1433
10.1002/anie.202109237
10.1039/D2CS00116K
10.1016/j.jsb.2021.107702
10.1038/s41467-021-27210-x
10.1038/s41592-020-00990-8
10.1016/j.chembiol.2021.05.005
10.1093/nar/gkab1174
10.1038/nature13527
10.1038/s41467-023-42233-2
10.1038/nature01456
10.1016/j.cell.2008.07.022
10.1038/s41589-019-0294-6
10.1021/acs.jmedchem.0c01845
10.1177/2472555220965528
10.1016/j.molcel.2021.01.023
10.1016/j.gpb.2022.11.008
10.1038/s41467-022-33575-4
10.1039/C8RA10436K
10.1016/bs.mie.2018.11.005
10.1021/acschembio.8b00692
10.1016/j.str.2017.04.009
10.1038/s41598-021-90770-x
10.1038/nsmb.2874
10.1074/jbc.274.17.12036
10.1146/annurev-biochem-090120-013613
10.1016/j.str.2014.12.014
10.1038/s41592-019-0575-8
10.1038/s41592-023-01853-8
10.1128/MCB.00097-16
10.1042/EBC20170041
10.1021/acscentsci.0c00049
10.1038/nature11376
10.1002/pro.4792
10.1016/j.molcel.2008.08.021
10.1146/annurev-biochem-060815-014922
10.1038/s41592-020-01049-4
10.1021/acschembio.5b00216
10.1021/acschembio.9b00092
10.1038/s41573-021-00245-x
10.1038/nbt.1511
10.1002/cmdc.202200615
10.1038/s41467-023-44237-4
10.1038/nprot.2006.468
10.1016/j.molcel.2024.01.022
10.1146/annurev-biochem-032620-104421
10.1016/j.cell.2008.09.049
10.1126/science.aar5839
10.1038/s41467-018-08027-7
10.1038/s41586-020-2000-y
10.1038/nmeth.4169
10.1038/s41586-021-03197-9
10.1038/nchembio.1858
10.1021/jacs.2c10784
10.1038/s41589-021-00878-4
10.1038/s41592-021-01220-5
10.1038/s41589-021-00952-x
10.1002/anie.201914396
10.1016/j.cell.2009.10.030
10.1038/s41586-020-2374-x
10.1016/j.molcel.2009.01.011
10.1039/D2CS00387B
10.1038/s41586-024-07089-6
10.1038/s41589-022-01177-2
10.1093/bioinformatics/btp033
10.1038/s42003-019-0437-z
10.1038/s41594-023-01206-1
10.1038/s41573-021-00371-6
10.1038/s41467-023-39904-5
10.1002/pro.4176
10.1038/s41571-023-00736-3
10.1016/S1097-2765(03)00452-0
10.1038/s41594-023-01146-w
10.1073/pnas.1407849111
10.1016/j.molcel.2010.02.025
10.1016/j.jmb.2015.09.014
10.1016/j.jbc.2022.101653
10.1007/978-1-0716-1665-9_5
10.1021/acs.jmedchem.1c00895
10.1107/S2059798318002425
10.1021/bi101913m
10.1016/j.str.2013.02.019
10.1093/nar/gkh340
ContentType Journal Article
DBID CGR
CUY
CVF
ECM
EIF
NPM
AAYXX
CITATION
7X8
DOI 10.1126/sciadv.ado6492
DatabaseName Medline
MEDLINE
MEDLINE (Ovid)
MEDLINE
MEDLINE
PubMed
CrossRef
MEDLINE - Academic
DatabaseTitle MEDLINE
Medline Complete
MEDLINE with Full Text
PubMed
MEDLINE (Ovid)
CrossRef
MEDLINE - Academic
DatabaseTitleList MEDLINE - Academic
CrossRef
MEDLINE
Database_xml – sequence: 1
  dbid: NPM
  name: PubMed
  url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 2
  dbid: EIF
  name: MEDLINE
  url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search
  sourceTypes: Index Database
DeliveryMethod fulltext_linktorsrc
Discipline Sciences (General)
EISSN 2375-2548
ExternalDocumentID 10_1126_sciadv_ado6492
39392888
Genre Journal Article
GroupedDBID 53G
5VS
AAFWJ
ACGFS
ADAXU
ADBBV
ADPDF
AENVI
AFPKN
ALMA_UNASSIGNED_HOLDINGS
AOIJS
BBORY
BCGUY
BCNDV
BKF
CGR
CUY
CVF
EBS
ECM
EIF
FRP
GROUPED_DOAJ
HYE
KQ8
M48
M~E
NPM
OK1
OVD
OVEED
RHF
RHI
RPM
TEORI
AAYXX
CITATION
7X8
ID FETCH-LOGICAL-c220t-6ce7bb8cbce88803228612d9aa3ed43ea698f7ccab4e3aeed6ad77d67a320c793
IEDL.DBID M48
ISSN 2375-2548
IngestDate Sat Oct 26 01:55:00 EDT 2024
Fri Dec 06 07:14:37 EST 2024
Sat Nov 02 12:25:20 EDT 2024
IsDoiOpenAccess false
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 41
Language English
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-c220t-6ce7bb8cbce88803228612d9aa3ed43ea698f7ccab4e3aeed6ad77d67a320c793
Notes ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ORCID 0000-0003-2465-0748
0000-0003-2068-8255
0000-0002-1362-191X
0000-0002-8654-1670
0000-0002-6239-5365
0000-0001-7113-9024
OpenAccessLink https://doi.org/10.1126/sciadv.ado6492
PMID 39392888
PQID 3115769898
PQPubID 23479
ParticipantIDs proquest_miscellaneous_3115769898
crossref_primary_10_1126_sciadv_ado6492
pubmed_primary_39392888
PublicationCentury 2000
PublicationDate 2024-Oct-11
2024-10-11
20241011
PublicationDateYYYYMMDD 2024-10-11
PublicationDate_xml – month: 10
  year: 2024
  text: 2024-Oct-11
  day: 11
PublicationDecade 2020
PublicationPlace United States
PublicationPlace_xml – name: United States
PublicationTitle Science advances
PublicationTitleAlternate Sci Adv
PublicationYear 2024
References e_1_3_2_26_2
e_1_3_2_49_2
e_1_3_2_28_2
e_1_3_2_41_2
e_1_3_2_64_2
e_1_3_2_87_2
e_1_3_2_20_2
e_1_3_2_43_2
e_1_3_2_62_2
e_1_3_2_85_2
e_1_3_2_22_2
e_1_3_2_45_2
e_1_3_2_68_2
e_1_3_2_24_2
e_1_3_2_47_2
e_1_3_2_66_2
e_1_3_2_89_2
e_1_3_2_60_2
e_1_3_2_83_2
e_1_3_2_81_2
e_1_3_2_9_2
e_1_3_2_16_2
e_1_3_2_37_2
e_1_3_2_7_2
e_1_3_2_18_2
e_1_3_2_39_2
e_1_3_2_54_2
e_1_3_2_75_2
e_1_3_2_10_2
e_1_3_2_31_2
e_1_3_2_52_2
e_1_3_2_73_2
e_1_3_2_5_2
e_1_3_2_12_2
e_1_3_2_33_2
e_1_3_2_58_2
e_1_3_2_79_2
e_1_3_2_3_2
e_1_3_2_14_2
e_1_3_2_35_2
e_1_3_2_56_2
e_1_3_2_77_2
e_1_3_2_50_2
e_1_3_2_71_2
e_1_3_2_90_2
e_1_3_2_27_2
e_1_3_2_48_2
e_1_3_2_29_2
e_1_3_2_40_2
e_1_3_2_65_2
e_1_3_2_86_2
e_1_3_2_21_2
e_1_3_2_42_2
e_1_3_2_63_2
e_1_3_2_84_2
e_1_3_2_23_2
e_1_3_2_44_2
e_1_3_2_69_2
e_1_3_2_25_2
e_1_3_2_46_2
e_1_3_2_67_2
e_1_3_2_88_2
e_1_3_2_61_2
e_1_3_2_82_2
e_1_3_2_80_2
e_1_3_2_15_2
e_1_3_2_38_2
e_1_3_2_8_2
e_1_3_2_17_2
e_1_3_2_59_2
e_1_3_2_6_2
e_1_3_2_19_2
e_1_3_2_30_2
e_1_3_2_53_2
e_1_3_2_76_2
e_1_3_2_32_2
e_1_3_2_51_2
e_1_3_2_74_2
e_1_3_2_11_2
e_1_3_2_34_2
e_1_3_2_57_2
e_1_3_2_4_2
e_1_3_2_13_2
e_1_3_2_36_2
e_1_3_2_55_2
e_1_3_2_78_2
e_1_3_2_2_2
e_1_3_2_91_2
e_1_3_2_72_2
e_1_3_2_70_2
References_xml – ident: e_1_3_2_86_2
  doi: 10.1007/s00249-021-01513-9
– ident: e_1_3_2_12_2
  doi: 10.1002/cmdc.202300464
– ident: e_1_3_2_20_2
  doi: 10.1146/annurev-pharmtox-022123-104147
– ident: e_1_3_2_14_2
  doi: 10.1038/nchembio.2329
– ident: e_1_3_2_18_2
  doi: 10.1038/s41589-018-0055-y
– ident: e_1_3_2_35_2
  doi: 10.1016/j.chembiol.2017.09.010
– ident: e_1_3_2_2_2
  doi: 10.1038/s41392-022-00966-4
– ident: e_1_3_2_10_2
  doi: 10.1126/science.aab1433
– ident: e_1_3_2_37_2
  doi: 10.1002/anie.202109237
– ident: e_1_3_2_19_2
  doi: 10.1039/D2CS00116K
– ident: e_1_3_2_62_2
  doi: 10.1016/j.jsb.2021.107702
– ident: e_1_3_2_33_2
  doi: 10.1038/s41467-021-27210-x
– ident: e_1_3_2_81_2
  doi: 10.1038/s41592-020-00990-8
– ident: e_1_3_2_44_2
  doi: 10.1016/j.chembiol.2021.05.005
– ident: e_1_3_2_58_2
  doi: 10.1093/nar/gkab1174
– ident: e_1_3_2_16_2
  doi: 10.1038/nature13527
– ident: e_1_3_2_71_2
  doi: 10.1038/s41467-023-42233-2
– ident: e_1_3_2_72_2
  doi: 10.1038/nature01456
– ident: e_1_3_2_50_2
  doi: 10.1016/j.cell.2008.07.022
– ident: e_1_3_2_36_2
  doi: 10.1038/s41589-019-0294-6
– ident: e_1_3_2_38_2
  doi: 10.1021/acs.jmedchem.0c01845
– ident: e_1_3_2_21_2
  doi: 10.1177/2472555220965528
– ident: e_1_3_2_66_2
  doi: 10.1016/j.molcel.2021.01.023
– ident: e_1_3_2_68_2
  doi: 10.1016/j.gpb.2022.11.008
– ident: e_1_3_2_34_2
  doi: 10.1038/s41467-022-33575-4
– ident: e_1_3_2_78_2
  doi: 10.1039/C8RA10436K
– ident: e_1_3_2_75_2
  doi: 10.1016/bs.mie.2018.11.005
– ident: e_1_3_2_41_2
  doi: 10.1021/acschembio.8b00692
– ident: e_1_3_2_13_2
  doi: 10.1016/j.str.2017.04.009
– ident: e_1_3_2_74_2
  doi: 10.1038/s41598-021-90770-x
– ident: e_1_3_2_17_2
  doi: 10.1038/nsmb.2874
– ident: e_1_3_2_48_2
  doi: 10.1074/jbc.274.17.12036
– ident: e_1_3_2_5_2
  doi: 10.1146/annurev-biochem-090120-013613
– ident: e_1_3_2_47_2
  doi: 10.1016/j.str.2014.12.014
– ident: e_1_3_2_80_2
  doi: 10.1038/s41592-019-0575-8
– ident: e_1_3_2_60_2
  doi: 10.1038/s41592-023-01853-8
– ident: e_1_3_2_65_2
  doi: 10.1128/MCB.00097-16
– ident: e_1_3_2_27_2
  doi: 10.1042/EBC20170041
– ident: e_1_3_2_43_2
  doi: 10.1021/acscentsci.0c00049
– ident: e_1_3_2_53_2
  doi: 10.1038/nature11376
– ident: e_1_3_2_83_2
  doi: 10.1002/pro.4792
– ident: e_1_3_2_56_2
  doi: 10.1016/j.molcel.2008.08.021
– ident: e_1_3_2_4_2
  doi: 10.1146/annurev-biochem-060815-014922
– ident: e_1_3_2_61_2
  doi: 10.1038/s41592-020-01049-4
– ident: e_1_3_2_9_2
  doi: 10.1021/acschembio.5b00216
– ident: e_1_3_2_30_2
  doi: 10.1021/acschembio.9b00092
– ident: e_1_3_2_67_2
  doi: 10.1038/s41573-021-00245-x
– ident: e_1_3_2_88_2
  doi: 10.1038/nbt.1511
– ident: e_1_3_2_46_2
  doi: 10.1002/cmdc.202200615
– ident: e_1_3_2_22_2
  doi: 10.1038/s41467-023-44237-4
– ident: e_1_3_2_87_2
  doi: 10.1038/nprot.2006.468
– ident: e_1_3_2_70_2
  doi: 10.1016/j.molcel.2024.01.022
– ident: e_1_3_2_6_2
  doi: 10.1146/annurev-biochem-032620-104421
– ident: e_1_3_2_51_2
  doi: 10.1016/j.cell.2008.09.049
– ident: e_1_3_2_85_2
  doi: 10.1126/science.aar5839
– ident: e_1_3_2_29_2
  doi: 10.1038/s41467-018-08027-7
– ident: e_1_3_2_31_2
  doi: 10.1038/s41586-020-2000-y
– ident: e_1_3_2_79_2
  doi: 10.1038/nmeth.4169
– ident: e_1_3_2_57_2
  doi: 10.1038/s41586-021-03197-9
– ident: e_1_3_2_11_2
  doi: 10.1038/nchembio.1858
– ident: e_1_3_2_24_2
  doi: 10.1021/jacs.2c10784
– ident: e_1_3_2_39_2
  doi: 10.1038/s41589-021-00878-4
– ident: e_1_3_2_63_2
  doi: 10.1038/s41592-021-01220-5
– ident: e_1_3_2_77_2
  doi: 10.1038/s41589-021-00952-x
– ident: e_1_3_2_42_2
  doi: 10.1002/anie.201914396
– ident: e_1_3_2_55_2
  doi: 10.1016/j.cell.2009.10.030
– ident: e_1_3_2_26_2
  doi: 10.1038/s41586-020-2374-x
– ident: e_1_3_2_49_2
  doi: 10.1016/j.molcel.2009.01.011
– ident: e_1_3_2_15_2
  doi: 10.1039/D2CS00387B
– ident: e_1_3_2_25_2
  doi: 10.1038/s41586-024-07089-6
– ident: e_1_3_2_45_2
  doi: 10.1038/s41589-022-01177-2
– ident: e_1_3_2_89_2
  doi: 10.1093/bioinformatics/btp033
– ident: e_1_3_2_82_2
  doi: 10.1038/s42003-019-0437-z
– ident: e_1_3_2_69_2
  doi: 10.1038/s41594-023-01206-1
– ident: e_1_3_2_7_2
  doi: 10.1038/s41573-021-00371-6
– ident: e_1_3_2_40_2
  doi: 10.1038/s41467-023-39904-5
– ident: e_1_3_2_52_2
  doi: 10.1002/pro.4176
– ident: e_1_3_2_3_2
  doi: 10.1038/s41571-023-00736-3
– ident: e_1_3_2_73_2
  doi: 10.1016/S1097-2765(03)00452-0
– ident: e_1_3_2_23_2
  doi: 10.1038/s41594-023-01146-w
– ident: e_1_3_2_54_2
  doi: 10.1073/pnas.1407849111
– ident: e_1_3_2_59_2
  doi: 10.1016/j.molcel.2010.02.025
– ident: e_1_3_2_91_2
  doi: 10.1016/j.jmb.2015.09.014
– ident: e_1_3_2_32_2
  doi: 10.1016/j.jbc.2022.101653
– ident: e_1_3_2_28_2
  doi: 10.1007/978-1-0716-1665-9_5
– ident: e_1_3_2_8_2
  doi: 10.1021/acs.jmedchem.1c00895
– ident: e_1_3_2_84_2
  doi: 10.1107/S2059798318002425
– ident: e_1_3_2_64_2
  doi: 10.1021/bi101913m
– ident: e_1_3_2_76_2
  doi: 10.1016/j.str.2013.02.019
– ident: e_1_3_2_90_2
  doi: 10.1093/nar/gkh340
SSID ssj0001466519
Score 2.3217244
Snippet Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously...
SourceID proquest
crossref
pubmed
SourceType Aggregation Database
Index Database
StartPage eado6492
SubjectTerms Bromodomain Containing Proteins
Cell Cycle Proteins - chemistry
Cell Cycle Proteins - metabolism
Cryoelectron Microscopy
Humans
Lysine - chemistry
Lysine - metabolism
Models, Molecular
Protein Binding
Proteolysis
Transcription Factors - chemistry
Transcription Factors - metabolism
Ubiquitin - metabolism
Ubiquitin-Conjugating Enzymes - chemistry
Ubiquitin-Conjugating Enzymes - metabolism
Ubiquitination
Von Hippel-Lindau Tumor Suppressor Protein - chemistry
Von Hippel-Lindau Tumor Suppressor Protein - metabolism
Title Mechanism of degrader-targeted protein ubiquitinability
URI https://www.ncbi.nlm.nih.gov/pubmed/39392888
https://www.proquest.com/docview/3115769898
Volume 10
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV1bS8MwFA4yX3wR53VeRgVBfcjY0ixpHkREHEOYTw72VpImgYK2bm3F_XtP0s4LKvgDEsh3cnq-05zzHYTOrDE8FFJhJ6aG4VIQLKjQmBrXlKatYdr1O08e2HhK72fD2Wf9UwNg8Wtq5-ZJTRdPvbf58hoc_upLA4zUrz2pc0YFfI7XCURFV941aai-_99CGRv6OR8k5EMMeVHUaDj-3OJ7jPqDePoANNpCmw1zDG5qU7fRmsm2UbvxzSK4aASkL3cQnxjXz5sWz0FuA-3kILRZ4Lro2-jAazOkWVCpdF6lpWufchWyy100Hd093o5xMyABJ4T0S8wSw5WKEpUYSGT74JsREBYtpAyNpqGRTESWg40UNaGEaMik5lwzLkPST8Az91AryzNzgIKEJJYwWOAGF8mBFcpKS7WIIqZYxG0Hna8giV9qHYzY5w-ExTV4cQNeB52uEIvhqrr3B5mZvCpiL-zjB1Z20H4N5cdeoQCiBoc4_MfqI7RBgFq4CDIYHKNWuajMCVCDUnV9St31ln8HkXG7MQ
link.rule.ids 314,780,784,864,2221,24318,27924,27925
linkProvider Scholars Portal
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Mechanism+of+degrader-targeted+protein+ubiquitinability&rft.jtitle=Science+advances&rft.au=Crowe%2C+Charlotte&rft.au=Nakasone%2C+Mark+A&rft.au=Chandler%2C+Sarah&rft.au=Craigon%2C+Conner&rft.date=2024-10-11&rft.issn=2375-2548&rft.eissn=2375-2548&rft.volume=10&rft.issue=41&rft.spage=eado6492&rft_id=info:doi/10.1126%2Fsciadv.ado6492&rft.externalDBID=NO_FULL_TEXT
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=2375-2548&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=2375-2548&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=2375-2548&client=summon