It is well known that cellular survival requires that numerous compounds travel across cellular membranes. Nutrients must be brought into the cell, metabolic end-products may be excreted, deleterious substances must be removed, and intercellular communication requires that signaling molecules exported from or imported into cellular structures. The majority of transmembrane traffic of small molecules across biological barriers is accomplished by membrane transport proteins, also known as transporters. These critical integral membrane proteins play important roles in a variety of biological functions including nerve impulse transmission, metabolism, and muscle contraction. Transporters are widely expressed in various organs and occupy an important position in the development of novel drug targets. Creative Biolabs is a leading company in the field of protein research and has been focused on the new drug targets discovery for many years. Therefore, we have accumulated some experience in the studies of membrane transporters and are glad to share it with our partners.
Structure of Membrane Transporters
Since the first X-ray crystal structure of membrane transporter was reported in 1996, many transporters have been analyzed, while the RCSB Protein Data Bank contains over 800 crystal structures categorized as transporters as of 2013. The majority of transporters contain 12 transmembrane regions and do not require multisubunit assemblies for activity. Members of the major facilitator superfamily (MFS) such as ATP-binding cassette transporters share this structural feature of transporters. However, transporters with fewer than 12 transmembrane domains still account for a significant portion of this class of proteins though they are less common.
Fig.1 The overall structure of Na+/K+ transporter(left), SERCA transporter(middle), and V-ATPase(right). (Almasi, 2020)
The Function of Membrane Transporters
In mammalian cells, the plasma membrane is a selectively permeable barrier that creates an intracellular environment and maintains cell stability and homeostasis, which is due to membrane transporters. Mechanistically, membrane transporters can be divided into two main categories: primary and secondary active transporters. Through ATP hydrolysis, primary active transporters move solutes against their electrochemical gradients. Instead, secondary active transporters utilize the energy stored in the electrochemical gradient of ions across the plasma membrane that was generated by the primary active transporters. Moreover, there are three basic types of membrane transporters, uniporter, symporters, and antiporters. Primary active transporters are often uniporter while secondary active transporters are classified as symporters or antiporters depending on the direction.
Fig.2 Different types of membrane transports. (Blass, 2015)
Membrane Transporters as Drug Targets
Because membrane transporters are essential for a plethora of cell functions ranging from cell homeostasis to clinical drug toxicity, this superfamily of proteins has emerged as novel therapeutic targets. Transporter inhibition can be accomplished by occupying the substrate-binding site with a substrate mimic that is not transported through the membrane, thus preventing transporter activity. Nowadays, therapeutics that target membrane transporters have been very successful in treating a variety of psychiatric disorders such as schizophrenia and depression. However, the side effects of membrane transporters inhibitors should attract enough attention.
As a kind of classical drug target, membrane transporters play a role in novel drug development. As an advanced biotech company, Creative Biolabs has paid attention to membrane transporter research aim to the discovery of novel drug targets. If you are interested in drug target development or other fields in therapeutic molecular development, please feel free to contact us.
Almasi, S.; et al. Exploring the therapeutic potential of membrane transport proteins: Focus on cancer and chemoresistance. Cancers. 2020, 12(6), 1624.
Blass, B. E. Basic principles of drug discovery and development. Elsevier. 2015.