8RFM

Human NOQ1 enzyme in complex with NADH by serial crystallography

8RFM の概要

• エントリーDOI: 10.2210/pdb8rfm/pdb
• 関連するPDBエントリー: 8RFN
• 分子名称: NAD(P)H dehydrogenase [quinone] 1, FLAVIN-ADENINE DINUCLEOTIDE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: nqo1, oxidoreductase, redox mechanism, flavoenzyme, flavoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 128099.49

構造登録者

Martin-Garcia, J.M.,Grieco, A.,Medina, M.,Boneta, S.,Pey, A.L. (登録日: 2023-12-13, 公開日: 2024-05-29)

主引用文献

Grieco, A.,Boneta, S.,Gavira, J.A.,Pey, A.L.,Basu, S.,Orlans, J.,Sanctis, D.,Medina, M.,Martin-Garcia, J.M.
Structural dynamics and functional cooperativity of human NQO1 by ambient temperature serial crystallography and simulations.
Protein Sci., 33:e4957-e4957, 2024

PubMed 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 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.

PubMed: 38501509
DOI: 10.1002/pro.4957

実験手法

X-RAY DIFFRACTION (2.7 Å)