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Studies of structural determinants of substrate binding in the Creatine Transporter (CreaT, SLC6A8) using molecular models.
- Source :
-
Scientific reports [Sci Rep] 2020 Apr 10; Vol. 10 (1), pp. 6241. Date of Electronic Publication: 2020 Apr 10. - Publication Year :
- 2020
-
Abstract
- Creatine is a crucial metabolite that plays a fundamental role in ATP homeostasis in tissues with high-energy demands. The creatine transporter (CreaT, SLC6A8) belongs to the solute carrier 6 (SLC6) transporters family, and more particularly to the GABA transporters (GATs) subfamily. Understanding the molecular determinants of specificity within the SLC6 transporters in general, and the GATs in particular is very challenging due to the high similarity of these proteins. In the study presented here, our efforts focused on finding key structural features involved in binding selectivity for CreaT using structure-based computational methods. Due to the lack of three-dimensional structures of SLC6A8, our approach was based on the realization of two reliable homology models of CreaT using the structures of two templates, i.e. the human serotonin transporter (hSERT) and the prokaryotic leucine transporter (LeuT). Our models reveal that an optimal complementarity between the shape of the binding site and the size of the ligands is necessary for transport. These findings provide a framework for a deeper understanding of substrate selectivity of the SLC6 family and other LeuT fold transporters.
- Subjects :
- Aquifex
Bacterial Proteins ultrastructure
Binding Sites
Creatine chemistry
Ligands
Nerve Tissue Proteins chemistry
Nerve Tissue Proteins ultrastructure
Plasma Membrane Neurotransmitter Transport Proteins chemistry
Plasma Membrane Neurotransmitter Transport Proteins ultrastructure
Protein Conformation, alpha-Helical
Sequence Alignment
Sequence Homology, Amino Acid
Serotonin Plasma Membrane Transport Proteins ultrastructure
Substrate Specificity
Creatine metabolism
Molecular Docking Simulation
Nerve Tissue Proteins metabolism
Plasma Membrane Neurotransmitter Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 32277128
- Full Text :
- https://doi.org/10.1038/s41598-020-63189-z