The earliest of a series of copper efflux genes in Escherichia coli are controlled by CueR, a member of the MerR family of transcriptional activators. Thermodynamic calibration of CueR reveals a zeptomolar (10 Ϫ21 molar) sensitivity to free Cu ϩ , which is far less than one atom per cell. Atomic details of this extraordinary sensitivity and selectivity for ϩ1 transition-metal ions are revealed by comparing the crystal structures of CueR and a Zn 2ϩ -sensing homolog, ZntR. An unusual buried

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... -receptor site in CueR restricts the metal to a linear, two-coordinate geometry and uses helix-dipole and hydrogenbonding interactions to enhance metal binding. This binding mode is rare among metalloproteins but well suited for an ultrasensitive genetic switch.