Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers.
Adenosine Diphosphate
/ metabolism
Adenosine Triphosphate
/ metabolism
Catalytic Domain
Cell Cycle Proteins
/ genetics
Cell Survival
/ genetics
Colorectal Neoplasms
/ enzymology
Crystallization
DNA
/ metabolism
DNA Damage
/ genetics
Gene Silencing
HCT116 Cells
Humans
Hydrolysis
Magnetic Resonance Spectroscopy
/ methods
Microsatellite Instability
Models, Molecular
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Proteins
/ genetics
Transfection
Werner Syndrome Helicase
/ chemistry
Zinc
/ metabolism
Polo-Like Kinase 1
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
26
05
2020
revised:
28
10
2020
accepted:
28
10
2020
entrez:
17
11
2020
pubmed:
18
11
2020
medline:
15
9
2021
Statut:
epublish
Résumé
Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable (MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.2-Å crystal structure of the WRN helicase core (517-1,093), comprising the two helicase subdomains and winged helix domain but not the HRDC domain or nuclease domains. The structure highlights unusual features. First, an atypical mode of nucleotide binding that results in unusual relative positioning of the two helicase subdomains. Second, an additional β-hairpin in the second helicase subdomain and an unusual helical hairpin in the Zn
Identifiants
pubmed: 33199508
pii: 4/1/e202000795
doi: 10.26508/lsa.202000795
pmc: PMC7671478
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Proto-Oncogene Proteins
0
Adenosine Diphosphate
61D2G4IYVH
Adenosine Triphosphate
8L70Q75FXE
DNA
9007-49-2
Protein Serine-Threonine Kinases
EC 2.7.11.1
WRN protein, human
EC 3.6.4.12
Werner Syndrome Helicase
EC 3.6.4.12
Zinc
J41CSQ7QDS
Banques de données
PDB
['2WWY', '3AAF', '6YHR']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106169/ZZ14/Z
Pays : United Kingdom
Informations de copyright
© 2020 Newman et al.
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