ArticlePloS one2011
Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.Nature genetics · 2016Pooled it
- Candidate gene association study suggests potential role of dopamine beta-hydroxylase in pain heterogeneity in sickle cell disease.Frontiers in genetics · 2023Article
- Formation of Unstable and very Reactive Chemical Species Catalyzed by Metalloenzymes: A Mechanistic Overview.Molecules (Basel, Switzerland) · 2019Review
- Article
- Characterization of SNPs in the dopamine-β-hydroxylase gene providing new insights into its structure-function relationship.Neurogenetics · 2017Article
- The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution.Science advances · 2016Article
- Chronic loss of noradrenergic tone produces β-arrestin2-mediated cocaine hypersensitivity and alters cellular D2 responses in the nucleus accumbens.Addiction biology · 2016Article
- Protein design: toward functional metalloenzymes.Chemical reviews · 2014Review
- Chronic neuroprotective effects of low concentration lithium on SH-SY5Y cells: possible involvement of stress proteins and gene expression.Neural regeneration research · 2014Review
- Dopamine β-hydroxylase inhibitors enhance the discriminative stimulus effects of cocaine in rats.The Journal of pharmacology and experimental therapeutics · 2013Article
- Cytochromes b561: ascorbate-mediated trans-membrane electron transport.Antioxidants & redox signaling · 2013Review
- The selective dopamine β-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2013Article
- Functional characterization of genetic enzyme variations in human lipoxygenases.Redox biology · 2013Article
- Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.PloS one · 2012Article
- De novo sequencing and transcriptome analysis of the central nervous system of mollusc Lymnaea stagnalis by deep RNA sequencing.PloS one · 2012Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHuman dopamine β-hydroxylase (DBH) is an important therapeutic target for complex traits. Several single nucleotide polymorphisms (SNPs) have also been identified in DBH with potential adverse physiological effect. However, difficulty in obtaining diffractable crystals and lack of a suitable template for modeling the protein has ensured that neither crystallographic three-dimensional structure nor computational model for the enzyme is available to aid rational drug design, prediction of functional significance of SNPs or analytical protein engineering. PRINCIPAL
findingsAdequate biochemical information regarding human DBH, structural coordinates for peptidylglycine alpha-hydroxylating monooxygenase and computational data from a partial model of rat DBH were used along with logical manual intervention in a novel way to build an in silico model of human DBH. The model provides structural insight into the active site, metal coordination, subunit interface, substrate recognition and inhibitor binding. It reveals that DOMON domain potentially promotes tetramerization, while substrate dopamine and a potential therapeutic inhibitor nepicastat are stabilized in the active site through multiple hydrogen bonding. Functional significance of several exonic SNPs could be described from a structural analysis of the model. The model confirms that SNP resulting in Ala318Ser or Leu317Pro mutation may not influence enzyme activity, while Gly482Arg might actually do so being in the proximity of the active site. Arg549Cys may cause abnormal oligomerization through non-native disulfide bond formation. Other SNPs like Glu181, Glu250, Lys239 and Asp290 could potentially inhibit tetramerization thus affecting function.
conclusionsThe first three-dimensional model of full-length human DBH protein was obtained in a novel manner with a set of experimental data as guideline for consistency of in silico prediction. Preliminary physicochemical tests validated the model. The model confirms, rationalizes and provides structural basis for several biochemical data and claims testable hypotheses regarding function. It provides a reasonable template for drug design as well.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.