title: An all-atom model of the structure of human copper transporter 1.
abstract: Human copper transporter 1 (hCTR1) is the major high affinity copper influx transporter in mammalian cells that also mediates uptake of the cancer chemotherapeutic agent cisplatin. A low resolution structure of hCTR1 determined by cryoelectron microscopy was recently published. Several protein structure simulation techniques were used to create an all-atom model of this important transporter using the low resolution structure as a starting point. The all-atom model provides new insights into the roles of specific residues of the N-terminal extracellular domain, the intracellular loop, and C-terminal region in metal ion transport. In particular, the model demonstrates that the central region of the pore contains four sets of methionine triads in the intramembranous region. The structure confirms that two triads of methionine residues delineate the intramembranous region of the transporter, and further identifies two additional methionine triads that are located in the extracellular N-terminal part of the transporter. Together, the four triads create a structure that promotes stepwise transport of metal ions into and then through the intramembranous channel of the transporter via transient thioether bonds to methionine residues. Putative copper-binding sites in the hCTR1 trimer were identified by a program developed by us for prediction of metal-binding sites. These sites correspond well with the known effects of mutations on the ability of the protein to transport copper and cisplatin.
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA 92093-0505. USA, itsigeln@ucsd.edu
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Sharikov
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Greenberg
authors.forename: Mark A
authors.initials: MA
authors.lastname: Miller
authors.forename: Valentina L
authors.initials: VL
authors.lastname: Kouznetsova
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Larson
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D002945:Cisplatin / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D000079923:Copper Transporter 1; D018360:Crystallography, X-Ray; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D003300:Copper; D002945:Cisplatin