000133349 001__ 133349
000133349 005__ 20240412150654.0
000133349 0247_ $$2doi$$a10.1002/pro.4957
000133349 0248_ $$2sideral$$a138067
000133349 037__ $$aART-2024-138067
000133349 041__ $$aeng
000133349 100__ $$aGrieco, Alice
000133349 245__ $$aStructural dynamics and functional cooperativity of human <scp>NQO1</scp> by ambient temperature serial crystallography and simulations
000133349 260__ $$c2024
000133349 5060_ $$aAccess copy available to the general public$$fUnrestricted
000133349 5203_ $$aThe 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 half‐reaction 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 free‐electron 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.
000133349 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E35-23R$$9info:eu-repo/grantAgreement/ES/MCIU-ERDF/RTI2018-096246-B-I00$$9info:eu-repo/grantAgreement/ES/MCIN/AEI/10.13039/501100011033$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-136369NB-I00
000133349 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000133349 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000133349 700__ $$aBoneta, Sergio
000133349 700__ $$aGavira, José A.
000133349 700__ $$aPey, Angel L.
000133349 700__ $$aBasu, Shibom
000133349 700__ $$aOrlans, Julien
000133349 700__ $$aSanctis, Daniele de
000133349 700__ $$0(orcid)0000-0001-8743-0182$$aMedina, Milagros$$uUniversidad de Zaragoza
000133349 700__ $$aMartin-Garcia, Jose Manuel
000133349 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000133349 773__ $$g33, 4 (2024), 22 pp.$$pProtein sci.$$tProtein science$$x0961-8368
000133349 8564_ $$s17342016$$uhttps://zaguan.unizar.es/record/133349/files/texto_completo.pdf$$yVersión publicada
000133349 8564_ $$s2214819$$uhttps://zaguan.unizar.es/record/133349/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000133349 909CO $$ooai:zaguan.unizar.es:133349$$particulos$$pdriver
000133349 951__ $$a2024-04-12-13:58:30
000133349 980__ $$aARTICLE