Estudo comparativo das estruturas dos transportadores da família SLC6

Abstract

The SLC6 family comprises sodium- and chloride-dependent solute transporters that play a key role in maintaining cellular homeostasis by mediating the transmembrane transport of neurotransmitters, amino acids, and other small solutes. These transporters are involved in several physiological processes and are clinically relevant therapeutic targets for the treatment of neurological and psychiatric disorders such as depression, schizophrenia, Parkinson’s disease, and epilepsy. This review presents a comprehensive overview of the functional and structural characteristics of the SLC6 family, with emphasis on the conserved LeuT-fold architecture and structural variations that influence substrate selectivity, transport dynamics, and drug recognition. Structural resolution techniques such as X-ray crystallography and cryo electron microscopy enabled the elucidation of three-dimensional structures at atomic resolution, revealing binding sites and regulatory domains. While crystallography provides high-resolution images, it is limited by the requirement for crystallization, particularly for membrane proteins. Cryo-electron microscopy overcomes this limitation by capturing multiple conformational states without crystallization, although resolution may be lower in flexible regions. For proteins without experimentally resolved structures, homology modeling was employed based on bacterial and eukaryotic templates such as LeuT, MhsT, and dDAT. The adopted methodology involved systematic data collection from structural databases, followed by comparative analysis of modeled and resolved transporters. Functional and pharmacological implications of the described structural elements were also discussed, contributing to the understanding of the molecular mechanisms that govern the operation of these transporters and reinforcing their potential as therapeutic targets.