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

      Protein Science : A Publication of the Protein Society
      Allosteric Regulation, drug effects, Allosteric Site, Aniline Compounds, chemistry, metabolism, pharmacology, therapeutic use, Antisickling Agents, Clinical Trials, Phase III as Topic, Crystallography, X-Ray, Drug Design, Hemoglobins, antagonists & inhibitors, isolation & purification, Humans, Hydrogen Bonding, Models, Molecular, Propionates, Protein Conformation, Structure-Activity Relationship, Water

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          Abstract

          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 A 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.

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