Reactivity of the human hemoglobin "dark side".

Ligand binding to the heme distal side is a paradigm of biochemistry. However, X-ray crystallographic studies highlighted the possibility that O2 and NO2- may bind to the proximal heme side of ferrous human hemoglobin (Hb) alpha-chains complexed with the alpha-hemoglobin stabilizing protein and to ferric human hemoglobin beta-chains, respectively. Strikingly, the role generally played by the proximal HisF8 residue is played by the distal HisE7 side chain forming the trans axial ligand of the hemeFe atom. This: i) brings to light that Hb may utilize both heme distal and proximal sides for ligand discrimination, ii) draws attention to the nonequivalence of alpha- and beta-chains, and iii) highlights the possibility that partially unfolded Hb derivatives may display transient ligand-binding properties different from those of the native globin.