Intercellular gap junction channels are formed by the end-to-end docking of two hemichannels, each comprised of a hexamer of connexin subunits. A Ca model (yellow ribbons) for the membrane spanning domain of the hemichannels was derived by combining the information from a computational analysis of connexin sequences, the results of more than a decade of biochemical studies, and the constraints provided by a 3D map derived by electron cryocrystallography (blue). While individually, none of these approaches provided high-resolution information, their sum yielded an atomic model that predicts how connexin mutations (red spheres) which result in diseases such as nonsyndromic deafness and Charcot-Marie-Tooth disease may interfere with formation of functional channels by disrupting helix-helix packing. (Molecular graphics by Michael E. Pique and Mark Yeager using AVS software.)