Solute Carriers (SLCs) represent a wide variety of membrane proteins, with over 400 members in more than 60 families(1), facilitating the transport of diverse molecules across cell membranes. Solute carrier proteins regulate key cellular processes including ion and nutrient uptake, and drug absorption, distribution, metabolism and excretion (ADME), making SLCs interesting therapeutic targets in drug discovery.
Having structures for the SLCs of interest may improve the understanding of their functional roles in health and disease, and may facilitate rational drug design and development.
However, SLCs three-dimensional structure determination is impaired by the known difficulties associated with expressing and purifying membrane proteins. While there are several examples of X-ray structures for this family of proteins, the crystallization process is usually difficult, and the resulting structure only represents a static snapshot, which may not capture the full transport cycle. Homology modeling, while valuable, often struggles due to the vast sequence divergence within the SLC superfamily.
Cryo-electron microscopy (cryo-EM) may represent a valuable alternative for SLCs structure determination and for expanding our understanding of SLCs structure and activity. Cryo-EM may allow resolving multiple dynamic conformations of SLCs in a single experiment, and provide tools to better understand their function in disease formation, signaling pathways, and interactions with other proteins.
Facilitate Rational Design of Solute Carrier Protein Modulators with High Resolution Cryo-EM Data Collection
High resolution cryo-EM analysis of SLCs can capture the proteins of interest in various conformations, from substrate-bound to occluded states, often in a single experiment.
Direct observation of how substrates interact with specific residues within the binding pocket may guide or accelerate the development of new drugs. Capturing intermediate states during the transport process may allow a more complete understanding of SLC function, thus paving the way for the development of drugs targeting specific steps.
Cryo-EM structures may also reveal previously unknown regulatory sites, opening doors for the design of allosteric modulators of SLC activity.
Structural knowledge and insights into the dynamics of these proteins may facilitate multiple aspects of the drug design and development process, including repurposing of existing drugs and a better understanding of drug resistance, ultimately providing new pathways for the development of next-generation drugs.
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