(A) Ribbons representation of the SUR1 subunit. Color scheme: TMD0, pink; TMD1-NBD1, blue; TMD2-NBD2, yellow. Mg2+-ADP and Mg2+-ATP are shown in stick model. (B) The NBD dimer viewed from the membrane. Mg2+-ADP and Mg2+-ATP bind to the consensus and degenerate ATPase sites, respectively, to generate an asymmetric NBD dimer. (C) Close-up view of the SUR1 consensus ATPase site. Top - Residues in contact with Mg2+-ADP are shown. The signature ‘LSGGQ’ motif in NBD1 is disengaged from the bound nucleotide, resulting in a relatively ‘open’ consensus ATPase site. Bottom - shows EM density corresponding to Mg2+-ADP as a blue mesh. (D). Close-up view of the SUR1 degenerate ATPase site. Top - Residues in contact with Mg2+-ATP are shown. The signature sequence in NBD2 is mutated to ‘FSQGQ’ and makes direct contacts with the bound ATP molecule. This results in a ‘closed’ degenerate ATPase site. Bottom - shows EM density corresponding to Mg2+-ATP as a blue mesh. (E) Structural changes in the glibenclamide (GBC)-binding pocket in the NBD-open and NBD-closed states. Top panel – The GBC-binding pocket mapped to the NBD-open SUR1 structure (PDB: 6BAA). Residues in contact the GBC are indicated by red spheres (Martin et al., 2017b). A surface representation of the modeled GBC molecule is shown (pink). Middle panel – GBC binding residues (yellow spheres) mapped onto the NBD-closed SUR1 in the quatrefoil form. GBC is shown to indicate potential steric clashes between the inhibitor and the transporter. Bottom panel – Superposition of the NBD-open and NBD-closed states of SUR1 showing the displacement of GBC-binding residues upon nucleotide binding. The superposition shown was obtained by alignment of the half-transporter from the NBD-closed and NBD-open SUR1 comprised of: TM9,10,12–14,17 and NBD2. Unless stated otherwise, the quatrefoil form is displayed in all panels.