1. Department of Medical Biophysics,
2. Banting and Best Department of Medical Research,
3. Department of Medical Genetics and Microbiology, University of Toronto, 112 College Street, Toronto, Ontario M5G 1L6, Canada
4. Structural Biology Center and Midwest Center for Structural Genomics, Biosciences Division, Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, Illinois 60439, USA
5. Structural Genomics Consortium, Botnar Research Centre, Oxford, Oxon OX3 7LD, UK
6. Structural Genomics Consortium, Banting Institute, 100 College Street, Toronto, Ontario M5G 1L5, Canada
7. Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA
8. †Present address: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA
9. *These authors contributed equally to this work

Correspondence to: Michael E. Maguire⁷Aled M. Edwards^1,2,3,4,6 Correspondence and requests for materials should be addressed to A.M.E. (Email: aled.edwards@utoronto.ca) or M.E.M. (Email: mem6@cwru.edu).

Abstract

The magnesium ion, Mg²⁺, is essential for myriad biochemical processes and remains the only major biological ion whose transport mechanisms remain unknown. The CorA family of magnesium transporters is the primary Mg²⁺ uptake system of most prokaryotes^{1, 2, 3} and a functional homologue of the eukaryotic mitochondrial magnesium transporter⁴. Here we determine crystal structures of the full-length Thermotoga maritima CorA in an apparent closed state and its isolated cytoplasmic domain at 3.9 Å and 1.85 Å resolution, respectively. The transporter is a funnel-shaped homopentamer with two transmembrane helices per monomer. The channel is formed by an inner group of five helices and putatively gated by bulky hydrophobic residues. The large cytoplasmic domain forms a funnel whose wide mouth points into the cell and whose walls are formed by five long helices that are extensions of the transmembrane helices. The cytoplasmic neck of the pore is surrounded, on the outside of the funnel, by a ring of highly conserved positively charged residues. Two negatively charged helices in the cytoplasmic domain extend back towards the membrane on the outside of the funnel and abut the ring of positive charge. An apparent Mg²⁺ ion was bound between monomers at a conserved site in the cytoplasmic domain, suggesting a mechanism to link gating of the pore to the intracellular concentration of Mg²⁺.

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