Structural and Functional Analyses of an Allosteric EYA2 Phosphatase Inhibitor That Has On-Target Effects in Human Lung Cancer Cells.
Allosteric Regulation
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Crystallography, X-Ray
Enzyme Inhibitors
/ chemistry
Humans
Intracellular Signaling Peptides and Proteins
/ antagonists & inhibitors
Lung Neoplasms
/ metabolism
Models, Molecular
Nuclear Proteins
/ antagonists & inhibitors
Protein Binding
Protein Domains
Protein Tyrosine Phosphatases
/ antagonists & inhibitors
Small Molecule Libraries
/ chemistry
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
01
11
2018
revised:
05
05
2019
accepted:
28
06
2019
pubmed:
10
7
2019
medline:
18
6
2020
entrez:
10
7
2019
Statut:
ppublish
Résumé
EYA proteins (EYA1-4) are critical developmental transcriptional cofactors that contain an EYA domain (ED) harboring Tyr phosphatase activity. EYA proteins are largely downregulated after embryogenesis but are reexpressed in cancers, and their Tyr phosphatase activity plays an important role in the DNA damage response and tumor progression. We previously identified a class of small-molecule allosteric inhibitors that specifically inhibit the Tyr phosphatase activity of EYA2. Herein, we determined the crystal structure of the EYA2 ED in complex with NCGC00249987 (a representative compound in this class), revealing that it binds to an induced pocket distant from the active site. NCGC00249987 binding leads to a conformational change of the active site that is unfavorable for Mg
Identifiants
pubmed: 31285279
pii: 1535-7163.MCT-18-1239
doi: 10.1158/1535-7163.MCT-18-1239
pmc: PMC6726557
mid: NIHMS1038649
doi:
Substances chimiques
Enzyme Inhibitors
0
Intracellular Signaling Peptides and Proteins
0
Nuclear Proteins
0
Small Molecule Libraries
0
protein phosphatase inhibitor-1
0
EYA2 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1484-1496Subventions
Organisme : NCI NIH HHS
ID : F99 CA234940
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA234940
Pays : United States
Organisme : NIDA NIH HHS
ID : R03 DA030559
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA180347
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS108396
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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