@misc{10481/91955,
year = {2024},
month = {3},
url = {https://hdl.handle.net/10481/91955},
abstract = {The human NQO1 (hNQO1) is a flavin adenine nucleotide (FAD)-dependent
oxidoreductase that catalyzes the two-electron reduction of quinones to hydroquinones,
being essential for the antioxidant defense system, stabilization of
tumor suppressors, and activation of quinone-based chemotherapeutics. Moreover,
it is overexpressed in several tumors, which makes it an attractive cancer
drug target. To decipher new structural insights into the flavin reductive halfreaction
of the catalytic mechanism of hNQO1, we have carried serial crystallography
experiments at new ID29 beamline of the ESRF to determine, to the
best of our knowledge, the first structure of the hNQO1 in complex with
NADH. We have also performed molecular dynamics simulations of free
hNQO1 and in complex with NADH. This is the first structural evidence that
the hNQO1 functional cooperativity is driven by structural communication
between the active sites through long-range propagation of cooperative effects
across the hNQO1 structure. Both structural results and MD simulations have
supported that the binding of NADH significantly decreases protein dynamics and stabilizes hNQO1 especially at the dimer core and interface. Altogether,
these results pave the way for future time-resolved studies, both at x-ray freeelectron
lasers and synchrotrons, of the dynamics of hNQO1 upon binding to
NADH as well as during the FAD cofactor reductive half-reaction. This knowledge
will allow us to reveal unprecedented structural information of the relevance
of the dynamics during the catalytic function of hNQO1.},
organization = {European Union NextGenerationEU/PRTR (Grant number CNS2022-135713)},
organization = {MCIN/AEI/10.13039/501100011033/ERDF (Grant number
MCIN/AEI/PID2022-136369NB-I00)},
organization = {Ayuda de Atracción y Retención de Talento Investigador from the Community of Madrid (Grant number 2019-T1/BMD-15552)},
organization = {ERDF/Spanish Ministry of Science, Innovation
and Universities-State Research Agency (Grant number
RTI2018-096246-B-I00)},
organization = {Consejería de Economía, Conocimiento,
Empresas y Universidad, Junta de Andalucía
(Grant number P18-RT-2413)},
organization = {ERDF/Counseling of Economic
Transformation, Industry, Knowledge and Universities
(Grant number B-BIO-84-UGR20)},
organization = {Gobierno de
Aragon (Grant number E35-23R)},
publisher = {John Wiley & Sons},
keywords = {Cooperativity},
keywords = {Flavoenzyme},
keywords = {Human NQO1},
title = {Structural dynamics and functional cooperativity of human NQO1 by ambient temperature serial crystallography and simulations},
doi = {10.1002/pro.4957},
author = {Grieco, Alice and Boneta, Sergio and Gavira Gallardo, José Antonio and Pey Rodríguez, Ángel Luis and Basu, Shibom and Orlans, Julien and de Sanctis, Daniele and Medina, Milagros and Martín-García, José Manuel},
}