OVERVIEW OF DRUG TRANSPORTER FAMILIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 2

drugs. Instead, their primary functions are to transport nutrients or endogenous
substrates, such as sugars, amino acids, nucleotides, and vitamins, or to protect the
body from dietary and environmental toxins. However, the specificity of these trans-
porters is not strictly restricted to their physiological substrates. Drugs that bear
significant structural similarity to the physiological substrates have the potential to be
recognized and transported by these transporters. As a consequence, these transporters
also play significant roles in determining the bioavailability, therapeutic efficacy, and
pharmacokinetics of a variety of drugs. Nevertheless, because drugs may compete
with the physiological substrates of these transporters, they are also likely to interfere
with the transport of endogenous substrates and consequently produce deleterious
effects on body homeostasis.

1.2. STRUCTURE AND MODEL OF DRUG TRANSPORTERS

Because of the involvement of transporters in all facets of drug absorption, excretion,
and toxicity, characterization of transporter structure can provide a scientific basis for
understanding drug delivery and disposition, as well as the molecular mechanisms of
drug interactions and interindividual and interspecies differences. However, compared
to soluble proteins, the atomic resolution crystal structures of membrane transporters
have been extremely difficult to obtain, for several reasons. First is the amphipathic
nature of the surface of the transporters, with a hydrophobic area in contact with
membrane phospholipids and polar surface areas in contact with the aqueous phases
on both sides of the membrane; second is the low abundance of many transporters in
the membrane, making it impossible to overexpress them, a prerequisite for structural
studies; and third is the inherent conformational flexibility of the transporters, making
it difficult to obtain stable crystals.
Due to these difficulties, high-resolution three-dimensional structures have been
obtained for only a limited number of transporters. For other transporters, three-
dimensional structures have been achieved through homology modeling. In this ap-
proach, similar folding patterns between any protein and one for which the crystal
structure is known enable the construction of a fairly accurate three-dimensional pro-
tein model of the unknown structure using the related crystal structure as a template
and modern computational techniques. Three-dimensional structures have revealed
that transporters have -helical structures of the membrane-spanning domains, and

some of the helices have irregular shapes with kinks and bends. Certain transporters
undergo substantial movements during the substrate translocation process. Construc-
tion of three-dimensional transporter models have provided insight into functional
mechanisms and molecular structures and enabled formulation of new hypotheses
regarding transporter structure and function, which may be validated experimentally.

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1.3. TRANSPORT MECHANISMS

Not only do different transporters reside in the membrane with different three-
dimensional structures, but they also transport their substrates through different