Molecular Basis of Metal-Ion Selectivity and Zeptomolar Sensitivity by CueR

Abstract

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 – 21 molar) sensitivity to free Cu + , which is far less than one atom per cell. Atomic details of this extraordinary sensitivity and selectivity for +1transition-metal ions are revealed by comparing the crystal structures of CueR and a Zn 2 + -sensing homolog, ZntR. An unusual buried metal-receptor site in CueR restricts the metal to a linear, two-coordinate geometry and uses helix-dipole and hydrogen-bonding interactions to enhance metal binding. This binding mode is rare among metalloproteins but well suited for an ultrasensitive genetic switch.