Review of 3D templates for in silico homology models of MATs: improved 3D model of hDAT

• Published in: Medicinal chemistry research 2022, Vol.31 (4), p.643-651
• Main Authors: Jones, Charles B., Dukat, Małgorzata
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Computational neuroscience; Crystal structure; Crystallization; Crystallography; Dopamine; Dopamine transporter; Homology; Inorganic Chemistry; Leucine; Medicinal Chemistry; Mental disorders; Monoamine transporter; Original Research; Pharmacology/Toxicology; Serotonin; Serotonin transporter; Three dimensional models; X-ray crystallography
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-022-02863-5

In the past 20 years there have been great leaps in the understanding of the structure and mechanism of monoamine transporters (MATs) owing to X-ray crystallography and cryo-EM. From the first breakthrough with the crystallization of the ortholog bacterial leucine transporter (LeuT) to more recent structures of the higher-identity drosophila dopamine transporter (dDAT) and human serotonin transporter (hSERT), the construction of better 3D computational models of hDAT has been pursued and is essential for the development of new medications for neuropsychiatric disorders associated with dopamine dysregulation. Previous and recent homology models of the yet to be crystallized hDAT have relied only on one template for generation. Here, we tabulated currently available crystal structures of MATs and then employed a multi template approach to generate a hDAT 3D homology model where contribution of individual templates account for missing structural features of single template models (i.e., EL2 in dDAT). Graphical abstract