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

Citation
Mk. Safo et al., High-resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector, PROTEIN SCI, 10(5), 2001, pp. 951-957
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
PROTEIN SCIENCE
ISSN journal
0961-8368 → ACNP
Volume
10
Issue
5
Year of publication
2001
Pages
951 - 957
Database
ISI
SICI code
0961-8368(200105)10:5<951:HCSODH>2.0.ZU;2-2
Abstract
The crystal structure of human deoxy hemoglobin (Hb) complexed with a poten t allosteric effector (2-[4-[[(3,5-dimethylanilino)carbonyl] methyl]phenoxy l -2-methylpropionic acid) = RSR-13) is reported at 1.85 Angstrom resolutio n. Analysis of the hemoglobin:effector complex indicates that two of these molecules bind to the central water cavity of deoxy Hb in a symmetrical fas hion, 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 effecters and the protein make significant contributions to the overall binding. Phy siologically, the interaction of RSR-13 with Hb results in increased oxygen delivery to peripheral tissues. Thus, this compound has potential therapeu tic application in the treatment of hypoxia, ischemia, and trauma-related b lood loss. Currently, RSR-13 is in phase III clinical trials as a radiosens itizing agent in the treatment of brain tumors. A detailed structural analy sis of this compound complexed with deoxy Hb has important implications for the rational design of future analogs.