High–resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector

The crystal structure of human deoxy hemoglobin (Hb) complexed with a potent allosteric effector (2‐[4‐[[(3,5‐dimethylanilino)carbonyl]methyl]phenoxy]‐2‐methylpropionic acid) = RSR‐13) is reported at 1.85 Å resolution. Analysis of the hemoglobin:effector complex indicates that two of these molecules bind to the central water cavity of deoxy Hb in a symmetrical fashion, and that each constrains the protein by engaging in hydrogen bonding and hydrophobic interactions with three of its four subunits. Interestingly, we also find that water‐mediated interactions between the bound effectors and the protein make significant contributions to the overall binding. Physiologically, the interaction of RSR‐13 with Hb results in increased oxygen delivery to peripheral tissues. Thus, this compound has potential therapeutic application in the treatment of hypoxia, ischemia, and trauma‐related blood loss. Currently, RSR‐13 is in phase III clinical trials as a radiosensitizing agent in the treatment of brain tumors. A detailed structural analysis of this compound complexed with deoxy Hb has important implications for the rational design of future analogs.