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Part-IIIAdvances Dihydropyridines and …line and a circle label the three definite players, while the close relatives, which may havea role in drug resistance, are also indicated on this evolutionary diagram.Figure-1. Phylogenic tree of the MDR- related ABC transporters. The thick linesrepresent the proteins definitively involved in multi-drug resistance.(Reproduced from reference-4)All ABC proteins contain at least three characteristic peptide sequences: the Walker Aand B motifs and the so-called ABC-signature sequence. Whereas the Walker motifs arepresent in several classes of ATP binding proteins, the presence of the signature region isdiagnostic for the ABC proteins. It is generally accepted that the minimum functional unitrequirement for an ABC transporter is the presence of two transmembrane domains(TMDs) and two ATP Binding Cassette (ABC) units. These may be present within onepolypeptide chain ("full transporters"), or within a membrane-bound homo- orheterodimer of "half transporters". 8-11,27,28 There are no high-resolution structural datapresently available for any mammalian ABC transporter; therefore computer modelingand laborious biochemical experiments are necessary to elucidate the position andorientation of membrane spanning segments and other domains within the polypeptidechain. Figure 2 presents the most plausible membrane topology models for the key MDR-ABC transporters. As shown in Figure 2, Pgp-MDR1 (ABCB1) is a "full transporter" withsix TM helices in both TMDs of the protein, each followed by an ABC domain. A similarmembrane topology has been predicted for ABCB4 (MDR3), and ABCB11 (sister Pgp)as well. 24-28390