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

Protein Science : a Publication of the Protein Society
Martin K SafoD J Abraham

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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Citations

Nov 4, 2010·Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology·Alessandra OlianasMariagiuseppina Pellegrini
Aug 15, 2006·The Journal of Physical Chemistry. a·Sarah M Tschampel, Robert J Woods
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Sep 28, 2010·International Journal of Biological Macromolecules·Jinyu LiXiaolei Zhu

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