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PDBsum entry 2ppo

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Lyase PDB id
2ppo
Jmol
Contents
Protein chain
107 a.a.
Waters ×137

References listed in PDB file
Key reference
Title Structural coupling between fkbp12 and buried water.
Authors S.Szep, S.Park, E.T.Boder, G.D.Van duyne, J.G.Saven.
Ref. Proteins, 2008, 74, 603-611. [DOI no: 10.1002/prot.22176]
PubMed id 18704951
Note: In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above have been manually determined.
Abstract
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.
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.
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.
The above figures are reprinted by permission from John Wiley & Sons, Inc.: Proteins (2008, 74, 603-611) copyright 2008.
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