Structural dynamics at the active site of the cancer-associated flavoenzyme NQO1 probed by chemical modification with PMSF.
PMSF
X-ray crystallography
cancer
flavoenzyme
human NQO1
Journal
FEBS letters
ISSN: 1873-3468
Titre abrégé: FEBS Lett
Pays: England
ID NLM: 0155157
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
02
08
2023
received:
05
07
2023
accepted:
29
08
2023
medline:
15
11
2023
pubmed:
20
9
2023
entrez:
19
9
2023
Statut:
ppublish
Résumé
A large conformational heterogeneity of human NAD(P)H:quinone oxidoreductase 1 (NQO1), a flavoprotein associated with various human diseases, has been observed to occur in the catalytic site of the enzyme. Here, we report the X-ray structure of NQO1 with phenylmethylsulfonyl fluoride (PMSF) at 1.6 Å resolution. Activity assays confirmed that, despite being covalently bound to the Tyr128 residue at the catalytic site, PMSF did not abolish NQO1 activity. This may indicate that the PMSF molecule does not reduce the high flexibility of Tyr128, thus allowing NADH and DCPIP substrates to bind to the enzyme. Our results show that targeting Tyr128, a key residue in NQO1 function, with small covalently bound molecules could possibly not be a good drug discovery strategy to inhibit this enzyme.
Identifiants
pubmed: 37726177
doi: 10.1002/1873-3468.14738
doi:
Substances chimiques
NAD(P)H Dehydrogenase (Quinone)
EC 1.6.5.2
NQO1 protein, human
EC 1.6.5.2
Phenylmethylsulfonyl Fluoride
57KD15003I
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2687-2698Informations de copyright
© 2023 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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