Figure 1. Stereo ribbon representation of MRP1-NBD1. (a) The F1-like ATP-binding core is shown in red, the specific ABC-_ sub-domain in orange, the central helix H1 in blue, helix H6 in cyan, helices H8 and H9 in magenta and the ABC-_ sub-domain in green. The ATP is represented in sticks and the Fo_Fc map contoured at 3_ is shown around the ATP. (b) ATP binding site. The residues in contact with ATP are shown in stick representation. Figures are generated using Pymol (DeLano, W.L. The PyMOL Molecular Graphics System (2002) Web site http://www.pymol.org).

Human multidrug resistance protein 1 (MRP1) is a membrane protein that belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 contributes to chemotherapy failure by exporting a wide range of anti-cancer drugs when over expressed in the plasma membrane of cells. Here, we report the first high-resolution crystal structure of human MRP1-NBD1. Drug efflux requires energy resulting from hydrolysis of ATP by nucleotide binding domains (NBDs). Contrary to the prokaryotic NBDs, the extremely low intrinsic ATPase activity of isolated MRP1-NBDs allowed us to obtain the structure of wild-type NBD1 in complex with Mg2+/ATP. The structure shows that MRP1-NBD1 adopts a canonical fold, but reveals an unexpected non-productive conformation of the catalytic site, providing an explanation for the low intrinsic ATPase activity of NBD1 and new hypotheses on the cooperativity of ATPase activity between NBD1 and NBD2 upon heterodimer formation.