ArticleActa crystallographica. Section D, Biological crystallography2014
Mapping the conformational space accessible to catechol-O-methyltransferase.
Article in Acta crystallographica. Section D, Biological crystallography, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 36 citations in OpenAlex.
- Evaluation of phytochemicals from Tamarindus indica as a potential catechol-O-methyltransferase (COMT) inhibitor: an in-silico approach for Parkinson's disease.Scientific reports · 2026Article
- Understanding domain swapping in the c-Src SH3 domain through hinge-loop mutagenesis.Acta crystallographica. Section D, Structural biology · 2025Article
- Structure-Based Identification of Kelch-like ECH-Associated Protein 1 as a Pharmacological Target of Electrophile-Containing Catechol-ACS pharmacology & translational science · 2024Article
- Systematic Investigation of Docking Failures in Large-Scale Structure-Based Virtual Screening.ACS omega · 2022Article
- 1-Hydroxy-2(1Molecules (Basel, Switzerland) · 2022Article
- Small molecule AX-024 reduces T cell proliferation independently of CD3ϵ/Nck1 interaction, which is governed by a domain swap in the Nck1-SH3.1 domain.The Journal of biological chemistry · 2020Article
- ALIXE: a phase-combination tool for fragment-based molecular replacement.Acta crystallographica. Section D, Structural biology · 2020Article
- Structural and biochemical characterization of Rv0187, an O-methyltransferase from Mycobacterium tuberculosis.Scientific reports · 2019Article
- Equatorial Active Site Compaction and Electrostatic Reorganization in Catechol-ACS catalysis · 2019Article
- Article
- Cloning and expression of a novel catechol-O-methyltransferase in common marmosets.The Journal of veterinary medical science · 2017Article
- Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase.PloS one · 2016Article
- Crystal structure of O-methyltransferase CalO6 from the calicheamicin biosynthetic pathway: a case of challenging structure determination at low resolution.BMC structural biology · 2015Article
- Structure and Biophysical Characterization of the S-Adenosylmethionine-dependent O-Methyltransferase PaMTH1, a Putative Enzyme Accumulating during Senescence of Podospora anserina.The Journal of biological chemistry · 2015Article
- Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).ACS medicinal chemistry letters · 2015Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Methylation catalysed by catechol-O-methyltransferase (COMT) is the main pathway of catechol neurotransmitter deactivation in the prefrontal cortex. Low levels of this class of neurotransmitters are held to be causative of diseases such as schizophrenia, depression and Parkinson's disease. Inhibition of COMT may increase neurotransmitter levels, thus offering a route for treatment. Structure-based drug design hitherto seems to be based on the closed enzyme conformation. Here, a set of apo, semi-holo, holo and Michaelis form crystal structures are described that define the conformational space available to COMT and that include likely intermediates along the catalytic pathway. Domain swaps and sizeable loop movements around the active site testify to the flexibility of this enzyme, rendering COMT a difficult drug target. The low affinity of the co-substrate S-adenosylmethionine and the large conformational changes involved during catalysis highlight significant energetic investment to achieve the closed conformation. Since each conformation of COMT is a bona fide target for inhibitors, other states than the closed conformation may be promising to address. Crystallographic data for an alternative avenue of COMT inhibition, i.e. locking of the apo state by an inhibitor, are presented. The set of COMT structures may prove to be useful for the development of novel classes of inhibitors.
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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.