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

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.

• Authors: M K Safo, C M Moure, J C Burnett, G S Joshi, D J Abraham
• Journal: Protein science : a publication of the Protein Society (Protein Sci) Vol. 10 Issue 5 Pg. 951-7 (May 2001) ISSN: 0961-8368 [Print] United States
• PMID: 11316875 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aniline Compounds
• Antisickling Agents
• Hemoglobins
• Propionates
• Water
• deoxyhemoglobin
• efaproxiral

Topics

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