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PDBsum entry 2cb5
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Contents |
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* Residue conservation analysis
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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 structure of human bleomycin hydrolase, A self-Compartmentalizing cysteine protease.
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Authors
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P.A.O'Farrell,
F.Gonzalez,
W.Zheng,
S.A.Johnston,
L.Joshua-Tor.
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Ref.
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Structure, 1999,
7,
619-627.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Bleomycin hydrolase (BH) is a cysteine protease that is found in all
tissues in mammals as well as in many other eukaryotes and prokaryotes. Although
its conserved cellular function is as yet unknown, human bleomycin hydrolase
(hBH) has clinical significance in that it is thought to be the major cause of
tumor cell resistance to bleomycin chemotherapy. In addition, it has been
reported that an allelic variant of hBH is genetically linked to Alzheimer's
disease. RESULTS: We have determined the crystal structures of wild-type hBH and
of a mutant form of the enzyme. The overall structure is very similar to that of
the previously determined yeast homolog, however, there is a striking difference
in the charge distribution. The central channel, which has a strong positive
electrostatic potential in the yeast protein, is slightly negative in hBH. We
have determined that hBH does not have the DNA-binding activity of the yeast
protein and that the enzyme is localized to the cytoplasm. CONCLUSIONS: The
difference in charge distribution between the yeast and human BH enzymes is most
likely responsible for the difference in DNA-binding activity. Nevertheless, the
C-terminal autoprocessing activity and the role of the C terminus as a
determinant for peptidase activity are conserved between the yeast and human
forms. The structure of hBH suggests that the putative Alzheimer's disease
linked variation does not directly alter the intrinsic peptidase activity.
Rather, the position of the mutation suggests that it could affect interactions
with another protein, which may modulate peptidase activity through
repositioning of the C terminus.
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Figure 3.
Figure 3. The C terminus of hBH. Residues 447–454 of the
wild-type protein, as well as the catalytic Cys73, are shown as
bonds colored according to atom type. The corresponding residues
of the Cys73→Ser/ΔGlu455 mutant protein are shown in cyan.
The sidechains of the catalytic residues His372 and Asp396 are
shown with yellow bonds, as is the sidechain of Gln67, which
stabilizes the oxyanion intermediate during catalysis.
Hydrogen-bond interactions of the mutant protein – between the
C-terminal alanine and the sidechain of Gln67 and the amide
nitrogen atoms of Ser73 and Trp74, and between Ser73 and the
backbone amide of residue 373 – are shown as dotted white
lines. Arrows indicate the Cα atoms of labeled residues. Gly451
is the elbow at which the C-terminal arm rotates and extends.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1999,
7,
619-627)
copyright 1999.
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