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PDBsum entry 1d5f
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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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Structure of an e6ap-Ubch7 complex: insights into ubiquitination by the e2-E3 enzyme cascade.
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Authors
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L.Huang,
E.Kinnucan,
G.Wang,
S.Beaudenon,
P.M.Howley,
J.M.Huibregtse,
N.P.Pavletich.
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Ref.
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Science, 1999,
286,
1321-1326.
[DOI no: ]
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PubMed id
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Abstract
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The E6AP ubiquitin-protein ligase (E3) mediates the human papillomavirus-induced
degradation of the p53 tumor suppressor in cervical cancer and is mutated in
Angelman syndrome, a neurological disorder. The crystal structure of the
catalytic hect domain of E6AP reveals a bilobal structure with a broad catalytic
cleft at the junction of the two lobes. The cleft consists of conserved residues
whose mutation interferes with ubiquitin-thioester bond formation and is the
site of Angelman syndrome mutations. The crystal structure of the E6AP hect
domain bound to the UbcH7 ubiquitin-conjugating enzyme (E2) reveals the
determinants of E2-E3 specificity and provides insights into the transfer of
ubiquitin from the E2 to the E3.
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Figure 2.
Fig. 2. The E6AP catalytic cysteine (Cys820) maps to the
interface between the N and C lobes of the hect domain. Residues
of the active-site loop and those that make N-C lobe contacts
are shown in yellow. N and C lobes are colored red and green,
respectively. The hinge region (residues 738 to 740) between the
N and C lobes is colored white. White dashed lines indicate
hydrogen bonds; red atoms, oxygen; blue, nitrogen; green,
sulfur.
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Figure 3.
Fig. 3. A broad cleft at the interface of the N and C lobes
contains highly conserved residues whose mutation reduces the
formation of the thioester or isopeptide bond. (A) The molecular
surface of the E6AP hect domain is colored according to the
conservation in 18 hect sequences: human E6AP, Nedd4, y032,
tr12, rat Urb1, Saccharomyces pombe Pub1, all five hect E3s of
Saccharomyces cerevisiae (Rsp5, Tom1, Ufd4, Hul4, and Hul5),
four hect proteins from Caenorhabditis elegans (GenBank
accession numbers BAA21847, CAA19508, CAA86773, and CAA91061),
and two Drosophila melanogaster hect proteins (the hyperplastic
disc protein and one with GenBank accession number AAD38975).
The two views are related by a rotation of ~80° about the
vertical axis. The view on the left has an orientation similar
to that of Fig. 1A; that on the right is similar to Fig. 2. The
position of the broad cleft is approximately marked by a black
line. [Prepared with the program GRASP (43).] (B) Close-up view
of the broad cleft. The N and C lobes of the hect domain are
colored red and green, respectively. The hinge region (738 to
740) between the N and C lobes is white; the conserved side
chains are yellow. The residues mutated in Angelman syndrome are
indicated with white spheres. Orientation is similar to that of
Fig. 1A.
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The above figures are
reprinted
by permission from the AAAs:
Science
(1999,
286,
1321-1326)
copyright 1999.
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