The relaxed
state (R3-state) of hemoglobin is stabilized by TD-1
via covalent and non-covalent bonding. (A) Structure of R3-state hemoglobin
with TD-1 as monomeric units (MUs, red sticks). α-chains of
hemoglobin are blue, and β-chains are yellow. Heme is not shown
for clarity. (B) Binding of MU-1/MU-1′ (red sticks) to β-Cys93
(orange sticks) induces large tertiary and quaternary structural perturbations.
Hemoglobin in the absence of MUs (R3 state, PDB code 1YZI) is shown
in white/gray and hemoglobin in the presence of MUs (PDB code 4NI0)
is shown in green. (C) Superposition of COHb without MUs (white ribbons)
and COHb-MU complex (green ribbons). MU-1 is shown as red sticks.
A magenta arrow represents the movement of β-His146 associated
with MU-1/MU-1′ binding of Cys93. (D) Interactions of MU-2/MU-2′,
MU-3/MU-3′, and MU-4/MU-4′ in the water cavity help
to tie the four hemoglobin subunits together.