The 3-dimensional structure of the human MDR1 P-gp membrane transporter. Structure-based sequence alignment of human MDR1 on the E coli MsbA ABC transporter (1JSQ) was performed using the Clustal W program (European Bioinformatics Institute, Hamburg, Germany). When the MDR1 sequence was analyzed using the tertiary structure prediction program 3D-PSSM (3-dimensional position-sensitive scoring matrix), it demonstrated the greatest concordance with 1JSQ, confirming that these transporters are structurally conserved. A structural model of human P-gp was created using 1JSQ as the template structure in Internal Coordinate Mechanism (ICM) software (Molsoft, San Diego, CA). The overall topologic architecture of the human MDR1 ABC transporter is predicted to have a similar tertiary structure to that of Eco-msbA, which is a homodimer. Each monomer is composed of 3 domains: a membrane-spanning domain (MSD), an intracellular domain (ICD), and a nucleotide binding domain (NBD). The transporter is approximately 1200 nm in length with the MSD being about 520 nm. The trans-membrane α-helices are tilted between 30° and 40° from the plane of the membrane, forming a cone-shaped structure with a substantial opening of about 250 nm on either side facing the lipid bilayer. The outer membrane leaflet half of the trans-membrane domain forms intermolecular contacts that hold the 2 monomers together by burying a solvent accessible area of about 8500 nm². The base of the chamber facing the cytoplasm is about 600 nm in the widest dimension (D.M., B. George, A.F.L., unpublished data, July 2003).