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PDBsum entry 1vev
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References listed in PDB file
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Key reference
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Title
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Novel conformational states of peptide deformylase from pathogenic bacterium leptospira interrogans: implications for population shift.
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Authors
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Z.Zhou,
X.Song,
W.Gong.
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Ref.
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J Biol Chem, 2005,
280,
42391-42396.
[DOI no: ]
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PubMed id
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Abstract
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Peptide deformylase is an attractive target for developing novel antibiotics.
Previous studies at pH 3.0 showed peptide deformylase from Leptospira
interrogans (LiPDF) exists as a dimer in which one monomer is in a closed form
and the other is in an open form, with different conformations of the CD-loop
controlling the entrance to the active pocket. Here we present structures of
LiPDF at its active pH range. LiPDF forms a similar dimer at pH values 6.5-8.0
as it does at pH 3.0. Interestingly, both of the monomers are almost in the same
closed form as that observed at pH 3.0. However, when the enzyme is complexed
with the natural inhibitor actinotin, the conformation of the CD-loop is
half-open. Two pairs of Arg109-mediated cation-pi interactions, as well as
hydrogen bonds, have been identified to stabilize the different CD-loop
conformations. These results indicate that LiPDF may be found in different
structural states, a feature that has never before been observed in the peptide
deformylase family. Based on our results, a novel substrate binding model,
featured by an equilibrium between the closed and the open forms, is proposed.
Our results present crystallographic evidence supporting population shift
theory, which is distinguished from the conventional lock-and-key or induced-fit
models. These results not only facilitate the development of peptide
deformylase-targeted drugs but also provide structural insights into the
mechanism of an unusual type of protein binding event.
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Figure 1.
FIGURE 1. Closed and half-open states of LiPDF. A, the
closed state within the active pH range represented by the
structure determined at pH 7.5. B, the half-open state bound
with actinonin. Shown on the right halves of both A and B, dimer
is formed through hydrophobic interactions (Phe^164, Phe^166,
Met^108, and Met^9 shown in stick model) between two subunits
colored in blue and brown, respectively. Shown on the left
halves of A and B are close-up pictures for the closed and
half-open pockets, respectively (viewed from same direction).
The CD-loop (residue 65-76) is highlighted in red, and the
active zinc ion is in pink. In the closed state (A), the
substrate pocket is blocked and hydrogen bonds are shown by a
green dashed line. For clarity, the formate group is shown as a
star. In the half-open state (B), the bound competitive
inhibitor actinonin is shown in stick-and-dots model. In this
state, Arg^71 is completely solvent-exposed and thus disordered.
This figure and Fig. 3 were prepared using Pymol.
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Figure 2.
FIGURE 2. Superposition of all LiPDF structures. A, all
observed conformational states of LiPDF are superimposed to
reveal the differences around the substrate pocket. Pink, closed
state at pH 3.0; brown, all closed states within pH values
6.5-8.0; blue, half-open state; cyan, open state at pH 3.0.
Residues Tyr^72 and Arg^109 (ball-and-stick model) undergo
significant conformational change during the conversion between
different states. The competitive inhibitor actinonin (black),
which was bound to the half-open state (blue) would collide with
the pocket in the closed states. With the opening of the
substrate pocket, the side chain of Arg^109 swung up toward the
molecular surface. Compared with the closed state at pH 3.0, the
closed states within the pH range 6.5-8.0 displayed a slightly
open pocket. B, a schematic is shown to help compare these
different states. The color scheme is consistent in both panels.
This figure was prepared using Molscript (30) and Raster3D (31).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
42391-42396)
copyright 2005.
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