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residues located in regions of the 2/2 fold that vary in the three groups, such
as the CD and FG segments and the amino-terminal part of the H-helix.
Further stabilizing interactions are provided by hydrogen bonds between
the haem and polar residues, involving Thr/Tyr at sites E2, E5, and EF6,
and by salt bridges involving haem propionates and Arg/Lys residues located
at position E10 in all 2/2Hbs, at position F2 in group I 2/2HbNs, and at
position F7 in group II 2/2HbOs (where F7 is invariantly Arg). It should
be noted that LysF7, despite being involved in electrostatic stabilization
of the haem also in group III
C. jejuni
2/2HbP, is not conserved in other
group III globins (
Nardini et al., 2006
). Further salt bridge interactions
may also derive from sequence-specific substitutions in the surroundings
of the haem propionates, as in the case of
M. tuberculosis
2/2HbN ArgE6,
and 2/2HbO ArgEF10. The crystallographic studies on group I 2/2HbNs
and group II 2/2HbOs have shown that haem isomerism (insertion of a frac-
tion of the haem groups into the globin structure in an inverted orientation)
may be present (
Milani et al., 2005
).
The conformation of the Fe-coordinated proximal HisF8 is typical of
an unstrained imidazole ring, with the imidazole plane lying in a staggered
azimuthal orientation relative to the haem pyrrole nitrogen atoms, thus
facilitating haem in-plane location of the iron atom, and supporting fast
oxygen association (
Bolognesi et al., 1997; Wittenberg et al., 2002
) and
electron donation to the bound distal ligand.
The 2/2Hb haem distal site cavity, hosting the exogenous ligands, is
characterized by unusual residues as compared to (non-)vertebrate globins.
It should be noted that in all 2/2Hbs, the E-helix falls close to the haem distal
face due to the 'pulling action' of the shortened CD region, thus causing side
chain crowding of the distal site residues at topological positions B10, CD1,
E7, E11, E14, E15, and G8. Among these, group-specific selections of
residues display polar character and allow the formation of networks of
hydrogen bonds functional to the stabilization of the diatomic haem ligand,
or implicated in the rebinding of dissociated ligands (
Samuni et al., 2003
).
Distal site polarity is expected to favour oxygen chemistry in the haem
crevice, as in peroxidases (
Hiner, Raven, Thorneley, Garc´a-C´novas, &
Rodr´guez-L´pez, 2002
).
There have been a number of experimental studies devoted to the
spectroscopic and structural characterization of the binding of several
diatomic ligands (CO, O
2
, NO, and cyanide) to the 2/2HbN in
M. tuberculosis
(
Couture, Yeh, et al., 1999; Milani, Ouellet, et al., 2004;
Ouellet, Milani, Couture, Bolognesi, & Guertin, 2006; Ouellet et al.,
