High-resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector.
Protein Sci
; 10(5): 951-7, 2001 May.
Article
em En
| MEDLINE
| ID: mdl-11316875
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 hemoglobineffector 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Propionatos
/
Hemoglobinas
/
Compostos de Anilina
Limite:
Humans
Idioma:
En
Ano de publicação:
2001
Tipo de documento:
Article