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PDBsum entry 3fns
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the histo-Aspartic protease (hap) from plasmodium falciparum.
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Authors
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P.Bhaumik,
H.Xiao,
C.L.Parr,
Y.Kiso,
A.Gustchina,
R.Y.Yada,
A.Wlodawer.
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Ref.
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J Mol Biol, 2009,
388,
520-540.
[DOI no: ]
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PubMed id
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Abstract
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The structures of recombinant histo-aspartic protease (HAP) from malaria-causing
parasite Plasmodium falciparum as apoenzyme and in complex with two inhibitors,
pepstatin A and KNI-10006, were solved at 2.5-, 3.3-, and 3.05-A resolutions,
respectively. In the apoenzyme crystals, HAP forms a tight dimer not seen
previously in any aspartic protease. The interactions between the monomers
affect the conformation of two flexible loops, the functionally important "flap"
(residues 70-83) and its structural equivalent in the C-terminal domain
(residues 238-245), as well as the orientation of helix 225-235. The flap is
found in an open conformation in the apoenzyme. Unexpectedly, the active site of
the apoenzyme contains a zinc ion tightly bound to His32 and Asp215 from one
monomer and to Glu278A from the other monomer, with the coordination of Zn
resembling that seen in metalloproteases. The flap is closed in the structure of
the pepstatin A complex, whereas it is open in the complex with KNI-10006.
Although the binding mode of pepstatin A is significantly different from that in
other pepsin-like aspartic proteases, its location in the active site makes
unlikely the previously proposed hypothesis that HAP is a serine protease. The
binding mode of KNI-10006 is unusual compared with the binding of other
inhibitors from the KNI series to aspartic proteases. The novel features of the
HAP active site could facilitate design of specific inhibitors used in the
development of antimalarial drugs.
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Figure 1.
Fig. 1. Inhibitors of HAP used in this study. (a) Chemical
diagrams of pepstatin A and KNI-10006. (b) Initial F[o] − F[c]
omit maps for pepstatin A and KNI-10006 contoured at the 1.9σ
level, with the final models superimposed.
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Figure 10.
Fig. 10. Active site of apo HAP and its complexes with
pepstatin A and KNI-10006. The active-site residues are shown in
stick representation. (a) A close-up view of the active site of
apo HAP. The Zn ion (purple) and the important water molecules
(pink) are shown as spheres. (b) A comparison of the active
sites of apo HAP and the metalloprotease DppA
(d-aminopeptidase). (c) A comparison of the active sites of apo
HAP (purple) and its complex with pepstatin A (cyan) based on a
superposition of protein C^α atoms. (d) A comparison of the
active sites of pepstatin A complexes of HAP (cyan) and pepsin
(orange). This superposition is based on protein C^α atoms. (e)
Overlay based on a superposition of the identical functional
groups in the active sites of HAP (cyan) and pepsin (orange)
complexed to pepstatin A. (f) Hydrogen bonding of the statine
hydroxyls with the catalytic residues in HAP (cyan) and pepsin
(orange). (g) Comparison of the active sites of HAP apoenzyme
(pink) and its complexes with pepstatin A (cyan) and KNI-10006
(green). Only the central statine residue of pepstatin A is
shown.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2009,
388,
520-540)
copyright 2009.
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