title: 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.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Safo
authors.forename: C M
authors.initials: CM
authors.lastname: Moure
authors.forename: J C
authors.initials: JC
authors.lastname: Burnett
authors.forename: G S
authors.initials: GS
authors.lastname: Joshi
authors.forename: D J
authors.initials: DJ
authors.lastname: Abraham
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000814:Aniline Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000986:Antisickling Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D018360:Crystallography, X-Ray; D015195:Drug Design; D006454:Hemoglobins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011422:Propionates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000986:Antisickling Agents; D006454:Hemoglobins; D011422:Propionates; D014867:Water; C100003:deoxyhemoglobin; C067396:efaproxiral