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 O(2) and NO(2) (-) may bind to the proximal heme side of ferrous human hemoglobin (Hb) α-chains complexed with the α-hemoglobin stabilizing protein and to ferric human hemoglobin β-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 heme-Fe 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 α- and β-chains, and iii) highlights the possibility that partially unfolded Hb derivatives may display transient ligand-binding properties different from those of the native globin.