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Figure 3.
Fig. 3. The CMG2 VWA domain is in an open conformation. (a)
The backbone structure of the CMG2 VWA domain (light green) was
superimposed onto the aligned structures of the  M
integrin I domains in their open (dark green, PDB ID code 1IDO
[PDB]
) and closed (blue, PDB ID code 1JLM [PDB]
) conformations (23, 26). The hydrophobic pockets I and II are
indicated by gray ovals and the Mg2+ ion for CMG2 is depicted as
a blue sphere. (b) The closed conformation of M with
Phe-302 buried in hydrophobic pocket I and Ile-316 buried in
hydrophobic pocket II. (c) The open conformation of M shows
a shift in the C-terminal helix from its position in b such that
Phe-302 becomes solvent-exposed, and hydrophobic pocket II is
now occupied by Leu-312. The positions of Phe-275 and Gly-243
have also shifted. (d) The structure of the CMG2 VWA domain is
similar to that of c and is therefore an open conformation. It
is hypothesized that the presence of Ile-213 bound in
hydrophobic pocket II and the absence of a downstream
hydrophobic residue equivalent to M Ile-316 might help
stabilize the open conformation. Residues that, when mutated,
result in ISH and JHF disease (Leu-45, Gly-105, Ile-189, and
Cys-218) are depicted in yellow. (e) In the closed structure of
M,
the Mn2+ ion (blue sphere) is coordinated by three waters, two
MIDAS serines, and an aspartic acid. The bond to the MIDAS
threonine has been broken.(f) In the open structure of M, the
Mg2+ ion is coordinated directly by two serines, two waters
(medium red spheres), a threonine, and a glutamate from a
neighboring monomer. (g) The coordination of the MIDAS metal in
the CMG2 VWA domain structure is identical to the coordination
observed for the open conformation of M shown in f.
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