2VQB

Bacterial flavin-containing monooxygenase in complex with NADP: soaking in aerated solution

Summary for 2VQB

• Entry DOI: 10.2210/pdb2vqb/pdb
• Related: 2VQ7
• Descriptor: FLAVIN-CONTAINING MONOOXYGENASE, FLAVIN-ADENINE DINUCLEOTIDE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: nadp, oxygen, flavin, drug metabolism, oxidoreductase
• Biological source: METHYLOPHAGA SP. SK1
• Total number of polymer chains: 4
• Total formula weight: 220829.86

Authors

Alfieri, A.,Malito, E.,Orru, R.,Fraaije, M.W.,Mattevi, A. (deposition date: 2008-03-12, release date: 2008-04-22, Last modification date: 2023-12-13)

Primary citation

Alfieri, A.,Malito, E.,Orru, R.,Fraaije, M.W.,Mattevi, A.
Revealing the Moonlighting Role of Nadp in the Structure of a Flavin-Containing Monooxygenase.
Proc.Natl.Acad.Sci.USA, 105:6572-, 2008

PubMed Abstract: Flavin-containing monooxygenases (FMOs) are, after cytochromes P450, the most important monooxygenase system in humans and are involved in xenobiotics metabolism and variability in drug response. The x-ray structure of a soluble prokaryotic FMO from Methylophaga sp. strain SK1 has been solved at 2.6-A resolution and is now the protein of known structure with the highest sequence similarity to human FMOs. The structure possesses a two-domain architecture, with both FAD and NADP(+) well defined by the electron density maps. Biochemical analysis shows that the prokaryotic enzyme shares many functional properties with mammalian FMOs, including substrate specificity and the ability to stabilize the hydroperoxyflavin intermediate that is crucial in substrate oxygenation. On the basis of their location in the structure, the nicotinamide ring and the adjacent ribose of NADP(+) turn out to be an integral part of the catalytic site being actively engaged in the stabilization of the oxygenating intermediate. This feature suggests that NADP(H) has a moonlighting role, in that it adopts two binding modes that allow it to function in both flavin reduction and oxygen reactivity modulation, respectively. We hypothesize that a relative domain rotation is needed to bring NADP(H) to these distinct positions inside the active site. Localization of mutations in human FMO3 that are known to cause trimethylaminuria (fish-odor syndrome) in the elucidated FMO structure provides a structural explanation for their biological effects.

PubMed: 18443301
DOI: 10.1073/PNAS.0800859105

Experimental method

X-RAY DIFFRACTION (2.8 Å)