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PDBsum entry 2ppo
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References listed in PDB file
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Key reference
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Title
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Structural coupling between fkbp12 and buried water.
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Authors
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S.Szep,
S.Park,
E.T.Boder,
G.D.Van duyne,
J.G.Saven.
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Ref.
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Proteins, 2008,
74,
603-611.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Globular proteins often contain structurally well-resolved internal water
molecules. Previously, we reported results from a molecular dynamics study that
suggested that buried water (Wat3) may play a role in modulating the structure
of the FK506 binding protein-12 (FKBP12) (Park and Saven, Proteins 2005;
60:450-463). In particular, simulations suggested that disrupting a hydrogen
bond to Wat3 by mutating E60 to either A or Q would cause a structural
perturbation involving the distant W59 side chain, which rotates to a new
conformation in response to the mutation. This effectively remodels the
ligand-binding pocket, as the side chain in the new conformation is likely to
clash with bound FK506. To test whether the protein structure is in effect
modulated by the binding of a buried water in the distance, we determined
high-resolution (0.92-1.29 A) structures of wild-type FKBP12 and its two mutants
(E60A, E60Q) by X-ray crystallography. The structures of mutant FKBP12 show that
the ligand-binding pocket is indeed remodeled as predicted by the substitution
at position 60, even though the water molecule does not directly interact with
any of the amino acids of the binding pocket. Thus, these structures support the
view that buried water molecules constitute an integral, noncovalent component
of the protein structure. Additionally, this study provides an example in which
predictions from molecular dynamics simulations are experimentally validated
with atomic precision, thus showing that the structural features of
protein-water interactions can be reliably modeled at a molecular level.
Proteins 2009. (c) 2008 Wiley-Liss, Inc.
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Figure 3.
Figure 3. The N-terminus of the helix moves toward the center
of the protein, with the main chain atoms from W59 and A60 of
the mutant moving by 1.28-1.74 Å (dotted lines). (Inset)
The C[  ]trace
of the E60A mutant (cyan) is shown against the surface rendering
of wild-type FKBP12 (purple), which is partially cut away to
reveal the protein core.
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Figure 5.
Figure 5. (a) FK506 (from PDB 1FKF) modeled in the
ligand-binding pocket of wild-type (violet) and E60Q (cyan)
FKBP12. The rotation of W59 leads to a conformation that creates
steric clash between its side chain and the docked FK506. (b)
The network of interacting amino acids and Wat3 in FKBP12.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2008,
74,
603-611)
copyright 2008.
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