title: The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution.
abstract: The norepinephrine pathway is believed to modulate behavioral and physiological processes, such as mood, overall arousal, and attention. Furthermore, abnormalities in the pathway have been linked to numerous diseases, for example hypertension, depression, anxiety, Parkinson's disease, schizophrenia, Alzheimer's disease, attention deficit hyperactivity disorder, and cocaine dependence. We report the crystal structure of human dopamine β-hydroxylase, which is the enzyme converting dopamine to norepinephrine. The structure of the DOMON (dopamine β-monooxygenase N-terminal) domain, also found in >1600 other proteins, reveals a possible metal-binding site and a ligand-binding pocket. The catalytic core structure shows two different conformations: an open active site, as also seen in another member of this enzyme family [the peptidylglycine α-hydroxylating (and α-amidating) monooxygenase], and a closed active site structure, in which the two copper-binding sites are only 4 to 5 Å apart, in what might be a coupled binuclear copper site. The dimerization domain adopts a conformation that bears no resemblance to any other known protein structure. The structure provides new molecular insights into the numerous devastating disorders of both physiological and neurological origins associated with the dopamine system.
authors.affiliation: Department of Chemistry, Kemitorvet 207, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Trine V
authors.initials: TV
authors.lastname: Vendelboe
authors.affiliation: Department of Chemistry, Kemitorvet 207, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Pernille
authors.identifier: 0000-0002-6806-4903
authors.initials: P
authors.lastname: Harris
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Yuguang
authors.identifier: 0000-0001-8916-8552
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Thomas S
authors.identifier: 0000-0002-0030-7235
authors.initials: TS
authors.lastname: Walter
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Karl
authors.identifier: 0000-0002-7266-4354
authors.initials: K
authors.lastname: Harlos
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Kamel
authors.identifier: 0000-0003-3506-6045
authors.initials: K
authors.lastname: El Omari
authors.affiliation: Department of Chemistry, Kemitorvet 207, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Hans E M
authors.identifier: 0000-0002-9540-8679
authors.initials: HE
authors.lastname: Christensen
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009638:Norepinephrine / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D003300:Copper; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine
keywords: Life sciences; biochemistry; biomolecules; crystal structure; dopamine; dopamine β-hydroxylase; neurochemistry; norepinephrine; structural biology