Structural dynamics at the active site of the cancer-associated flavoenzyme NQO1 probed by chemical modification with PMSF.

Autor: Grieco A; Department of Crystallography & Structural Biology, Institute of Physical Chemistry Blas Cabrera, Spanish National Research Council (CSIC), Madrid, Spain., Ruiz-Fresneda MA; Department of Microbiology, University of Granada, Granada, Spain., Gómez-Mulas A; Department of Physical Chemistry, University of Granada, Granada, Spain., Pacheco-García JL; Department of Physical Chemistry, University of Granada, Granada, Spain., Quereda-Moraleda I; Department of Crystallography & Structural Biology, Institute of Physical Chemistry Blas Cabrera, Spanish National Research Council (CSIC), Madrid, Spain., Pey AL; Department of Physical Chemistry, University of Granada, Granada, Spain.; Department of Physical Chemistry, Unit of Excellence in Applied Chemistry to Biomedicine and Environment, and Institute of Biotechnology, University of Granada, Granada, Spain., Martin-Garcia JM; Department of Crystallography & Structural Biology, Institute of Physical Chemistry Blas Cabrera, Spanish National Research Council (CSIC), Madrid, Spain.
Jazyk: angličtina
Zdroj: FEBS letters [FEBS Lett] 2023 Nov; Vol. 597 (21), pp. 2687-2698. Date of Electronic Publication: 2023 Sep 30.
DOI: 10.1002/1873-3468.14738
Abstrakt: 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.
(© 2023 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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