title: Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site.
abstract: 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.
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91190 Gif-sur-Yvette, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Ramaen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leulliot
authors.forename: Christina
authors.initials: C
authors.lastname: Sizun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ulryck
authors.forename: Olivier
authors.initials: O
authors.lastname: Pamlard
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Lallemand
authors.forename: Herman van
authors.initials: Hv
authors.lastname: Tilbeurgh
authors.forename: Eric
authors.initials: E
authors.lastname: Jacquet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019281:Dimerization; D006639:Histidine / Q000378:metabolism; D006801:Humans; D008274:Magnesium / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D009711:Nucleotides; D001224:Aspartic Acid; D006639:Histidine; D000255:Adenosine Triphosphate; D008274:Magnesium